Page 1 of 49 Diabetes

EPITOPE STEALING AS MECHANISM OF DOMINANT PROTECTION

BY HLA-DQ6 IN TYPE 1 DIABETES

Menno van Lummel1, David T. P. Buis1, Cherish Ringeling1, Arnoud H. de Ru1,

Jos Pool1, George K. Papadopoulos2, Peter A. van Veelen1, Helena Reijonen3,

Jan W. Drijfhout1 and Bart O. Roep1, 3

1Department of Immunohematology and Blood Transfusion,

Leiden University Medical Center, the Netherlands, The Netherlands;

2Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus

Institute of Technology, Arta, Greece

3Department of Diabetes Immunology, Diabetes & Metabolism Research Institute at the

Beckman Research Institute, City of Hope, Duarte, USA;

*Running title: islet epitope stealing by protective HLA-DQ6

Corresponding author:

Prof. Bart O Roep, PhD

Department of Immunohematology and Blood Transfusion, LUMC,

E3-Q, PO Box 9600, 2300 RC Leiden, the Netherlands

Tel: +31.71.5266673; Fax: +31.71.5266801; Email: [email protected]

Keywords: type 1 diabetes, HLA-DQ6, HLA-DQ8, protection, immunotherapy

1

Diabetes Publish Ahead of Print, published online January 9, 2019 Diabetes Page 2 of 49

ABSTRACT

The heterozygous DQ2/8 (DQA1*05:01-DQB1*02:01/DQA1*03:01-DQB1*03:02) genotype confers the highest risk in T1D, whereas the DQ6/8 (DQA1*02:01-DQB1*06:02/

DQA1*03:01-DQB1*03:02) genotype is protective. The mechanism of dominant protection by DQ6 (DQB1*06:02) is unknown. We tested the hypothesis that DQ6 interferes with peptide- binding to DQ8 by competition for islet epitope (‘epitope stealing’) by analysis of the islet ligandome presented by HLA-DQ6/8 and -DQ8/8 on dendritic cells pulsed with islet autoantigens preproinsulin (PPI), GAD65 and IA2, followed by competition assays employing a newly established ‘epitope stealing’ HLA/peptide binding assay. HLA-DQ ligandome analysis revealed a distinct DQ6 peptide-binding motif compared to the susceptible DQ2/8 molecules. PPI and IA-2 peptides were identified from DQ6, of DQ6/8 heterozygous DC, but no DQ8 islet peptides were retrieved. Insulin B6-23, a highly immunogenic CD4 T-cell epitope in T1D patients bound to both DQ6 and DQ8. Yet, binding of InsB6-23 to DQ8 was prevented by DQ6. We obtained first functional evidence of a mechanism of dominant protection from disease, where HLA molecules associated with protection bind islet epitopes in a different, competing, HLA-binding register, leading to ‘epitope stealing’ and conceivably diverting the immune response from islet epitopes presented by disease susceptible HLA molecules in the absence of protective HLA.

2 Page 3 of 49 Diabetes

INTRODUCTION

The strongest single genetic determinant of type 1 diabetes (T1D) risk resides in the HLA class

II region. Specifically, DQA1*05:01-DQB1*02:01 (hereafter denoted as DQ2) and

DQA1*03:01-DQB1*03:02 (DQ8) have been found to be the major susceptible haplotypes in

most populations, whereas DQA1*02:01-DQB1*06:02 (DQ6) has been described to be

protective in a dominant manner. Most notably, the risk of the DQ2/8 heterozygote genotype

is markedly increased (~5-fold) compared to individual DQ2 and DQ8 homozygous genotypes,

indicating an epistatic or synergistic effect The other T1D-critical HLA-DQ molecule is DQ6

that is strongly associated with dominant protection from T1D.

The dominant protective role of HLA-DQ6 in T1D has been well documented but its

mechanism remains unclear until today. Several plausible mechanistic explanations may apply;

those that rely upon αβ pairings between DQ8 or DQ2 and DQ6 are most likely not operative

since these pairings do not form (1). Rather, we favoured epitope stealing as most conceivable

mechanism. Epitope stealing may occur whereby protective HLA bind critical auto antigenic

peptides, thereby preventing binding by susceptible HLA molecules in such a manner (e.g.

higher affinity) that the pathway to autoantigen presentation and disease is inhibited (2). The

peptide-binding characteristics of DQ6 have been studied based upon three-dimensional

models of DQ6 molecules, by molecular modelling of DQ6 eluted peptides and by eluting

natural processed and presented insulin peptides (3-6). These studies suggest that T1D high-

risk DQ molecules bind a distinct peptide repertoire as compared to the protective DQ6

molecule. (7; 8). Recently, we defined the peptide-binding motifs of high-risk HLA-DQ

molecules (9); the high-risk DQ8cis molecule harbours peptide-binding motifs having a

preference for binding peptides with negatively charged amino acids in the p1 and p9 pocket

and mainly aliphatic residues at the other anchor positions in the HLA peptide-binding grooves.

However, we already have proof-of concept that a prototype proinsulin epitope (proinsB6-23)

can bind both DQ8 and DQ6 with overlapping amino acids in proinsB6-23 (10). In the same 3 Diabetes Page 4 of 49

study, HLA-DQ8 restricted CD4 T cells reactive against proinsB6-23 cells were isolated from a new-onset HLA-DQ8 homozygous T1D patient. The phenotype of these CD4 T cells changed from pro-inflammatory (IFN-) to anti-inflammatory (IL-10) in the presence of antigen- presenting cells expressing the high-risk HLA-DQ8cis as well as the protective HLA-DQ6.

Here, we deciphered the DQ6 peptidome of the major islet antigens PPI, IA-2 and GAD65 and the protective mechanism of DQ6 in T1D. First, we studied in detail the peptide-binding characteristics of DQ6 and compared its binding motif with the established binding motifs of the high-risk HLA-DQ molecules. Next, we examined the capacity of DQ6 to prevent binding of islet epitopes to high-risk HLA-DQ8. Finally, we explored the effect of DQ6 on the islet ligandome and on specific antigen presentation by DQ8 co-expressed by the same antigen- presenting cells (dendritic cells), including an examination of ‘epitope-stealing’. This new knowledge reinforces the concept of using immunomodulatory antigen-presenting cells carrying the protective HLA-DQ6 molecule as targets of T1D therapy.

4 Page 5 of 49 Diabetes

RESEARCH DESIGN AND METHODS

Culture of B-cell lines. Epstein-Barr virus transformed B-lymphoblastoid cell lines (EBV-

BLCL) homozygous for DQ6 (LD2B, MGAR) or DQ8 (DUCAF, BSM) or heterozygous for

DQ6/8 (CST), were generated from B cells of healthy individuals (11). For HLA-DQ-peptide

binding assays, EBV-BLCL were harvested by centrifugation, washed three times with PBS

and lysed with NP-40 lysis buffer; for HLA-DQ peptidome analysis BLCL were lysed using

zwitter detergent. To remove nuclei and insoluble material lysates were centrifuged at 3500

RPM for 20 min at 4°C. Lysates were stored at -80oC. Lysates were used for HLA-DQ-peptide

binding assays and HLA-DQ peptide elution studies.

Islet autoantigens. Recombinant islet autoantigens were produced as described previously

(12; 13).

HLA-DQ affinity purification and peptide elutions and peptidome analysis. To decipher

the peptide-binding characteristics of DQ6, affinity purifications and peptidome analysis of

HLA-DQ6-expressing mDC were performed as described previously (9). Affinity-purification

of HLA-DQ6 or DQ8 molecules from islet autoantigen pulsed DQ6/8 heterozygous mDC and

subsequent peptide elutions were performed as follows. The HLA-peptide elution protocol was

optimized for low mDC numbers according to our existing protocol for EBV-BLCL. All HLA-

DQ isolation and washing steps were performed using a 100µL pipet tip. Lysate was precleared

using 100µL Sepharose beads. HLA-DQ8 was isolated using Sepharose beads coupled with

the DQ8-capturing antibody IVD12 (Department of Immunohematology and Blood

Transfusion). Subsequently, from the same lysate HLA-DQ6 molecules were isolated using

SPV-L3 (Department of Immunohematology and Blood Transfusion) coupled to Sepharose

beads. mDC lysates were passed sequentially over the IVD12 and SPV-L3 Sepharose columns.

Columns were washed as previously described (9). DQ-peptide complexes were eluted with 5 Diabetes Page 6 of 49

two bed volumes 10% acetic acid. The HLA-DQ eluates (containing both peptides and HLA)

were fractionated with an HPLC system. The material was eluted using a gradient of 0-50%

acetonitrile supplemented with 0.1% trifluoroacetic acid.

Peptide identification by mass spectrometry. Natural processed and presented peptides

(NPPP) eluted from HLA-DQ molecules were analysed as described previously (13).

Molecular modelling. HLA-DQ homology modelling of the complexes between eluted

peptides and the DQ6 molecule were performed as described previously (10).

Hybridomas and affinity purification of HLA-DQ specific antibodies. Hybridomas

producing the pan-DQ monoclonal antibody (Moab) SPV-L3 or the HLA-DQ8 specific

monoclonal antibody IVD12 were first cultured in IMDM supplemented with 8% FCS,

penicillin/streptomycin and L-glutamine. Gradually FCS was depleted from the IMDM

medium by diluting the cultures with protein-free hybridoma medium (PFHM) until cells were

cultured in 100% PFHM. The IVD12 hybridoma did not survive in the absence of FCS and

therefore PFHM was supplemented with 1% FCS. For antibody production, hybridomas were

cultured in PFHM in CELLine Bioreactor Flasks (CL1000; Sigma-Aldrich) according to the

manufacturer’s instructions. SPV-L3 was affinity purified from PFHM medium using protein

A Sepharose and Moab IVD12 using protein G Sepharose. Protein concentration was

determined by A280 spectrophotometry.

HLA-DQ peptide binding assays. To obtain an indicator peptide for the HLA-DQ6-peptide

binding studies, core-nonamers of a selection of peptides eluted from HLA-DQ6 EBV-BLCL

were predicted by molecular modelling. The core-nonamers, containing the anchor residues

crucial for HLA-class II binding, were synthesized with 2 flanking alanines both at the N- and 6 Page 7 of 49 Diabetes

C-terminus including a biotin label at the N-terminus. The flanking alanine residues (forming

14-mer peptides) are essential for peptide-binding outside the HLA class II binding grooves.

Binding studies were further performed as described previously (8). HLA-DQ6 and -DQ8

competitive peptide-binding assays were performed as described previously (13) that we took

as a starting point to set up the epitope-stealing assay where DQ6 interference on binding a

peptide to DQ8 can be examined. In this assay, peptide binding to HLA-DQ8, HLA-DQ6 or

DQ6/8 is measured using a specific DQ8 or DQ6 indicator peptide. 96 well plates are coated

with the pan-DQ antibody SPV-L3 and lysates from homozygous DQ6/6, DQ8/8 or

heterozygous DQ6/8 BLCL are incubated overnight at 4oC. After washing and blocking the

plates, fixed concentrations of DQ8 or DQ6 indicator peptides (0.6µM) are incubated in the

presence of increasing concentrations of test-peptide (InsB6-23) that can bind both DQ8 and

DQ6 (0-900µM). For the DQ8/8 or DQ6/6 plate, once the test peptide binds to HLA, the

indicator peptide is outcompeted and a drop in signal (counts per minute; CPM) is measured.

To measure InsB6-23 binding to DQ8 in the presence of DQ6, binding of the test-peptide to

the DQ6/8 coated plate is measured in the presence of the DQ6 or DQ8 specific biotinylated

(Z) indicator peptide (DQ6 indicator: ZAAVKGSSLHVGAA; DQ8 indicator:

ZEEPRAPWIEQEGPEYWDQE [EPRAP]). Once InsB6-23 binds to DQ6, the DQ8 specific

indicator peptide will not be outcompeted by InsB6-23, a drop in signal is not measured

resulting in a stable signal. However, in the presence of the DQ6 specific indicator peptide, a

drop in signal will be observed once InsB6-23 binds preferentially DQ6 and not DQ8 and thus

outcompetes the DQ6 indicator peptide. DQ6 competition is defined as InsB6-23 binding to

the DQ6/8 coated plate in the presence of the DQ8-specific indicator peptide; DQ8 competition

is defined as InsB6-23 binding to DQ6/8 in the presence of the DQ6-specific indicator peptide.

Generation of dendritic cells. For elution of natural processed and presented islet peptides

from HLA-DQ expressing professional antigen presenting cells, generation of dendritic cells 7 Diabetes Page 8 of 49

(DC) from heterozygous HLA-DQ6/8 healthy blood donors was performed as described previously (13; 14). iDCs were pulsed with the islet autoantigens PPI, IA-2 and GAD65 for 6 hrs and iDC were matured with LPS (100ng/mL) for 24 hrs in the continuous presence of the three islet-autoantigens. After 30 hrs pulsed mDC were harvested, washed three times with

PBS to remove excess islet-autoantigens and lysed in 1mL zwitter lysis buffer and subsequently high-speed centrifuged for 60min at 10,000 x g to remove nuclei and insoluble material. For each HLA-DQ type a total of approximately 40x106 pulsed mDC were obtained from three donors.

8 Page 9 of 49 Diabetes

RESULTS

Ligandome of HLA-DQ6. The nine-mer putative peptide-binding cores of protective HLA-

DQ6 were deduced from the unique peptides eluted from homozygous DQ6 expressing EBV-

BLCL as we described previously for the T1D high-risk HLA-DQ molecules (9). In total

7.5*109 EBV-BLCL were used for the HLA/peptide elution studies. In total, 601 1156 unique

peptides from DQ6 were eluted (Supplemental Table 1). These number of unique peptides

eluted from DQ6 EBV-BLCL are consistent with the number of eluted peptides eluted from

EBV-BLCL expressing the susceptible HLA-DQ molecules as we described previously (9). A

unique peptide is defined as a peptide sequence that is unique to a protein; peptides with the

same amino acid sequence can be detected by mass spectrometry multiple times (called hits),

but such a particular peptide is than denoted as one unique peptide detected. Table 1 shows

examples of the alignment and core predictions (with anchor and non-anchor residues) of

length variants of eluted peptides from DQ6. Anchor and non-anchor residues in the minimal

binding registers of the unique DQ6 peptide sequences were predicted. Molecular modelling

studies with DQ6 were performed to verify the predictions of anchor and non-anchor residues

(data not shown). Based on the prediction of the minimal binding cores and the molecular

simulation studies, the frequency of the amino acids at both the anchor and non-anchor residues

in the eluted peptides was calculated for DQ6. Amino acids with a frequency of 1.5 times

higher than the same amino acids in the human proteome were considered as preferred residues

(Supplemental Figure 1). To visualize all amino acids in the peptide-binding binding groove

(positions p1-p9) of DQ6 (referred to as binding motif), heatmaps were generated (Figure 1).

To provide a proper comparison of both protective and high-risk HLA-DQ molecules, the

heatmaps of the HLA-DQ2/8 cis/trans molecules are included. Our previous studies showed

that the high-risk HLA-DQ8cis has a strong preference for negatively charged amino acids

(D/E) at the anchor positions p1 and p9. The binding motif of the protective DQ6 shows several

similarities with the high-risk HLA-DQ molecules. Small aliphatic residues such as G, A and 9 Diabetes Page 10 of 49

V are dominantly present, similar as for the DQ2/8 molecules. The negatively charged amino

acids D and E is are virtually absent at the anchor positions p4, p6 and p9 of DQ6, where HLA-

DQ2/8 molecules prefer such negatively charged residues. However Importantly, similarities

are observed between the peptide-binding preferences of protective DQ6 and susceptible DQ8;

a p9E p8E can be present in a DQ6 binding peptide and an E at this p8 position within a DQ6-

binding peptide is also important for peptide binding to DQ8cis (Figure 1 and Supplemental

Figure 1). The basic amino acids K, R and H are virtually absent at the anchor positions of the

protective HLA-DQ6 similar to the high-risk HLA-DQ2/8 molecules.

In conclusion, the peptide-binding requirements for DQ6 show that peptides can bind both

protective DQ6 as well as susceptible DQ8cis, which is a requirement for the hypothesized

mechanism of epitope stealing.

Epitope stealing by protective HLA-DQ6. CD4 T cells from a homozygous HLA-DQ8 T1D

patient responded against the prototype InsB6-23 epitope in the presence of DQ8 homozygous

APC with a pro-inflammatory phenotype (10). Yet, CD4 T-cells reactive against InsB6-23 in

the presence of HLA-DQ6/8 heterozygous APC elicited a cytokine production profile shifted

from a pro-inflammatory to an anti-inflammatory profile. Here, we hypothesise that protective

DQ6 bind autoantigens in a different (competing) binding register leading to ‘epitope stealing’

thereby inducing a regulatory, rather than a pathogenic immune response. To examine the

possibility that DQ6 ‘steals’ the InsB6-23 epitope from DQ8, we set up an HLA-DQ/epitope-

stealing assay based on our existing HLA-peptide binding assays (9) (graphic representation of

this assay with extended explanation in Supplemental Figure 2).A DQ6-specific indicator

peptide was chosen from a selection of DQ6 eluted peptide that bound with an intermediate

affinity to DQ6 and not to DQ8 (data not shown). Figure 2 shows that InsB6-23 can bind DQ6/6

or DQ8/8 with an EC50 of 0.11±0.01 and 3.6±0.6 µM, respectively. When both DQ6 and DQ8 are present (DQ6/8), binding of InsB6-23 to DQ8 was not observed (DQ6 competition). DQ8 10 Page 11 of 49 Diabetes

did not interfere with binding of InsB6-23 to DQ6 (DQ8 competition). Here, we show that

protective DQ6 interferes with binding of the diabetogenic InsB6-23 epitope to T1D high-risk

DQ8.

DQ6 interferes with binding of natural processed epitopes presented by DQ8 expressed

on dendritic cells. Epitopes derived from islet-autoantigens are generally presented by HLA

class II molecules after naturally processing by professional antigen-presenting cells APC (15).

Dendritic cells are essential for initiation of diabetogenic T cell responses and T1D

development. Recently, we showed that DQ2/8 heterozygous APC naturally process and

present PPI and IA-2 peptides recognized by proinflammatory autoreactive CD4 T cells in T1D

patients (13). To investigate if DQ6 interferes with binding of PPI and IA-2 peptides to DQ8

here we analysed the HLA-DQ6/8 islet peptidome by pulsing immature DC heterozygous for

HLA-DQ6/8 with PPI, IA-2 and GAD65. From these heterozygous HLA-DQ6/8 and pulsed

mDC, HLA-DQ8 was first immune precipitated using the HLA-DQ-specific antibody IVD12

subsequently followed by immune precipitation of HLA-DQ6 using the pan-DQ antibody

SPV-L3. HLA-eluted peptides were identified employing mass spectrometry. To confirm

HLA-DQ specificity of IVD12 and SPV-L3, stainings with homozygous HLA-DQ6 (MGAR)

and HLA-DQ8 (BSM) EBV-BLCL were performed. As shown in Supplemental Figure 3,

IVD12 solely recognizes HLA-DQ8 expressed on BSM, whereas SPV-L3 recognizes both

HLA-DQ6 and HLA-DQ8 expressed on MGAR and BSM, respectively.

From DQ8, PPI, IA-2 or GAD65 peptides were not identified. From DQ6 peptides derived

from PPI and IA-2 and not from GAD65 were identified (Figure 3). From PPI, several peptides

of the signal sequence were identified with a mean length of 12 amino acids (range 9-16).

Interestingly, a similar PPI signal peptide was identified by us naturally presented by DQ2/8

heterozygous DC (13); this peptide was recognized by proinflammatory CD4 T cells isolated

from both DQ8 homozygous and DQ2/8 heterozygous T1D patients. Now, for the first time 11 Diabetes Page 12 of 49

PPI signal peptides are identified as naturally processed DQ6 presented peptides. Naturally

processed and presented peptides by DQ6 were identified encompassing four core regions of

IA-2, including its transmembrane region. No peptides were identified from the C-terminus of

IA-2. These IA-2 core regions were distinct from the core regions of which peptides were

identified presented by DQ8 homozygous and DQ2/8 heterozygous DC. Here, we show that

protective DQ6 interferes with peptide binding to T1D high-risk DQ8.

Binding confirmation of naturally processed and DQ6 presented peptides. The anchor

residues and minimal binding registers of the DQ6 identified naturally processed and presented

peptides were in silico predicted using the DQ6 and DQ8 peptide-binding motifs (Figure 1) using our in-house MOTIFS software program. Anchor residues for DQ6 but not for DQ8 were predicted for all DQ6 eluted peptides (Table 2). First, an indicator peptide for DQ6 was selected to be able to perform competitive peptide-binding assays. Core-nonamers, predicted from a selection of 9 peptides eluted from DQ6 EBV-BLCL, were extended with alanine residues and labelled with biotin and tested in direct DQ6-peptide binding assays (Supplemental Figure 4).

The peptide with sequence ZAAVKGSSLHVGAA was selected as indicator peptide for the competitive peptide binding assays. Next, binding of the peptides eluted from DQ6/8 heterozygous DC to DQ6 was measured in competitive HLA-DQ-peptide binding assays as described previously (13). The following binding affinities (EC50) were calculated: PPI14-22

10.2±1.2 µM, IA-2374-386 4.6±1.2 µM, IA-2498-511 21.3±2.4 µM, IA-2543-566 23.2±7.3 µM and

IA-2582-593 7.6±0.6 µM (Supplemental Figure 5). Binding of these tested PPI and IA-2 peptides

to DQ8 was not observed. These data show exclusive binding of the eluted peptides by

protective DQ6 expressed on DQ6/8 heterozygous DC.

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DISCUSSION

We provide a functional explanation for epitope stealing as a mechanism for genetic protection

in type 1 diabetes (T1D) where DQ6 (DQB1*06:02) prevents binding of diabetogenic epitopes

by high-risk DQ8 as target of autoreactive CD4 T cells in T1D patients. First, DQ6 shows

peptide-binding characteristics enabling this molecule to bind and present similar islet epitopes

also presented by DQ8. Second, the prototype proinsulin epitope InsB6-23 binds both DQ6 and

DQ8, yet having a strong preference for binding DQ6 in the presence of DQ8. Finally, we

provide evidence that DQ6 interferes with binding of naturally processed and DQ8-presented

islet epitopes on the surface of DQ6/8 heterozygous DC. This DQ6 interference in peptide

presentation by DQ8 on the same antigen-presenting cell is due to sharing a similar PPI

peptidome, but also by having a distinct IA-2 peptidome.

The identified PPI signal peptides naturally processed and presented by DQ6 showed profound

similarities to the PPI signal peptide (PPI15-24) recently identified by us as a natural epitope

presented by DQ2/8 heterozygous DC. CD4 T cells isolated from T1D patients either being

DQ8 or DQ2/8 positive responded against this epitope (13). Here, we show that the same signal

peptide, although with a different binding register, can be naturally presented by DQ6. Peptide-

binding studies confirmed binding of the signal peptide to DQ6. Importantly, we show that in

the presence of DQ6 on the surface of DQ6/8 heterozygous DC, PPI signal peptides are not

eluted from DQ8. This is the first time ever that a study provides evidence for ‘epitope stealing’

where DQ6 steals a diabetogenic naturally processed epitope normally presented by DQ8.

InsB6-23 was not detected in the present study as an NPPP, which can be due to many technical

restrictions making it yet unable to elute and detect certain possibly low-quantitative peptide-

epitopes. However, a shorter variant - InsB9-23 (PPI 76-90) - has been identified as a natural

processed and eluted HLA-class II peptide and as target for CD8 T cells (16-18). Also, our

T1D patient derived T-cells clones reactive against InsB6-23 cross-react with naturally

processed insulin. Recently, we reported that the TCR of these T-cells cloned into T-cells of 13 Diabetes Page 14 of 49

humanized mice develop insulitis and cause selective beta-cell destruction in these mice, mimicking T1D (19). This observation underscores that the InsB peptide is made in vivo, and actually has biological and potentially pathological relevance.

The natural IA-2 peptides eluted from DQ6 encompassed four distinct core regions of the N- terminal part as well as the transmembrane region of IA-2. IA-2 peptides from DQ8, isolated from the same pulsed DQ6/8 DC, were not identified. Binding of the IA-2 peptides was confirmed for DQ6 and no binding was observed for DQ8. This finding is supported by our previous findings that DQ8 presents a set of natural IA-2 peptides, although different from the

DQ6-presented peptides, also derived from the N-terminus of IA-2 (13). Here, instead of steeling peptides from DQ8 as for the PPI signal peptides, DQ6 completely abrogates the presentation of IA-2 peptides by DQ8 on the same DQ6/8 heterozygous antigen-presenting cell. Interestingly, the same epitope stealing mechanism as described for InsB6-23, might here as well contribute to stealing of IA-2 peptides from susceptible DQ8 by protective DQ6.

GAD65 peptides were neither retrieved from DQ6 or from DQ8, although uptake of all three islet antigens was confirmed by proteome analysis of the pulsed DC (data not shown).

Recently, we showed that DQ8 homozygous DC did not present naturally processed and presented GAD65 peptides (13). This might imply that GAD65 peptides are not primary targets of autoreactive HLA-DQ-restricted CD4 T cells (pro- and anti-inflammatory) in T1D patients.

Intriguingly, as HLA-DQ8 is in linkage disequilibrium with HLA-DR4 (DRB1*04:01), this might argue that GAD65 epitopes may be presented by HLA-DR4 rather than HLA-DQ8 molecules. In support of this notion, in our previous study (12) where we eluted islet antigenic peptides from pulsed DC we sequentially purified HLA-DQ and HLA-DR and we were able to elude GAD65 peptides from HLA-DR4, supporting the notion that GAD65 autoimmunity in T1D might be restricted by HLA-DR.

14 Page 15 of 49 Diabetes

Additionally, not investigated in the present study, DQ6 is in linkage disequilibrium with HLA-

DR15 (DRB1*15:01) and as such a role for DR15 in the protection from T1D cannot be

excluded thus far.

Since dendritic cells were pulsed with islet autoantigens, one might expect an

overrepresentation of eluted peptides from these antigens. However, this was not our

observation; the majority of eluted peptides did not originate from the islet autoantigens. An

explanation for this observation could be competition between endogenous processed peptides

and peptides generated from the pulsed autoantigens. First, the pulsed autoantigens first have

to be taken up by the DC before being processed and presented by HLA class II molecules

already creating a disadvantage versus endogenous processed peptides. Second, affinity

differences likely play a role in HLA binding of endogenous processed and presented peptides

and peptides generated from the pulsed autoantigens.

T1D is a multifactorial disease whereby genetic factors inherited from the parents such as

protective HLA-DQ6 and environmental factors reduce the risk of developing T1D (8; 20; 21).

A new protective environmental factor with genetic implications could be the tolerizing effect

of non-inherited maternal antigens (NIMA) (22-24). The NIMA effect supports tolerance

induction to specific non-inherited protective HLA from the mother in the offspring (25). The

protective effect of HLA-DR13 as NIMA in rheumatoid arthritis has been found (26; 27).

Intriguingly, in our family cohort of children with T1D the number of cases where mothers

carry protective HLA-DQ6 is much reduced, suggesting that HLA-DQ6 could protect

offspring, even if the offspring does not inherit DQ6. As mechanism we propose the induction

of mixed chimerism in which maternal leukocytes carrying DQ8 (shared with the fetus) and

DQ6 (not inherited by the fetus) crossing the placenta could modulate the immune response in

the fetus, possibly by mechanisms including epitope stealing. The disease protective effect of

HLA-DQ6 as NIMA may be mimicked later in life by using immunomodulatory antigen

presenting cells (APC) carrying the protective DQ6 loaded with DQ6-specific islet epitopes in 15 Diabetes Page 16 of 49

addition to high-risk HLA-DQ8 shared with the patient. To translate this concept clinically for

T1D patients, it is essential to understand the protective mechanism of these specific HLA- subclasses as well as to delineate the natural islet peptidome of protective DQ6 in the context of DQ8.

Understanding the mechanism of dominant protection by DQ6 opens doors to novel immunotherapies which employ epitope stealing as a protective mechanism for T1D.

Candidate immunomodulatory APC are mesenchymal stromal cells (MSC), which have immunosuppressive and regenerative capacity. Beneficial effects of MSC transplantation in experimental models of T1D have been reported: MSC dampen autoreactive T cell responses

(28), enhance development of regulatory T cells (29; 30) and promote islet repair of endogenous or transplanted islets (31; 32). MSC that are hypo immunogenic and regulatory by nature, expressing DQ6 and DQ8 could be used to install tolerance in DQ8 positive T1D patients. As such, they resemble the way that mothers carrying DQ6 and DQ8 protect their

DQ8 inherited children from T1D by microchimerism (NIMA). In our view, this is an

“experiment of nature” showing that the maternal protective haplotype during pregnancy indirectly protects a child from destructive autoimmunity later in life. The potential of MSC to reduce proinflammatory autoimmune reactivity in an antigen-dependent fashion has not yet been explored. Therefore, it is attractive to mimic nature by exploring new therapeutic approaches using MSC matched for DR4/DQ8 with the recipient but mismatched with the protective DR15/DQ6 haplotype and loaded with our identified DQ6 natural peptides. Natural peptides presented by DQ6 should be tested for their capacities to induce antigen-specific regulatory T cells. This will provide a novel antigen-specific immunomodulatory therapy for the treatment of T1D patients to benefit from genetic protection endorsed by DQ6.

16 Page 17 of 49 Diabetes

ACKNOWLEDGEMENTS

This work was supported by the Juvenile Diabetes Research Foundation (17-2012-547), the

European Union’s 7th Framework Programme (FP7/2007-2013) under grant agreement

n°241447 (NAIMIT) and by a VICI grant of The Netherlands organization for scientific

research (VICI, 918.86.611) and an Expert Center Grant from the Dutch Diabetes Research

Foundation. BOR is director of the Wanek Family Project to Cure Type 1 Diabetes. We thank

Kees Franken from the Department of Immunohematology and Blood Transfusion for technical

advice regarding generation recombinant proteins. ML and BOR conceived experiments,

researched data, wrote and reviewed the manuscript. AR, DB, CR, GKP and JP researched

data. PV and JWD contributed to discussion and reviewed/edited the paper. BOR supervised

this study and contributed to discussion and writing the paper. BOR is the guarantor of this

work and, as such, had full access to all the data in the study and takes responsibility for the

integrity of the data and the accuracy of the data analysis. No potential conflicts of interest

relative to this article are reported.

17 Diabetes Page 18 of 49

REFERENCES

1. Kwok WW, Kovats S, Thurtle P, Nepom GT: HLA-DQ allelic polymorphisms constrain patterns of class II heterodimer formation. JImmunol 1993;150:2263-2272 2. Nepom GT, Kwok WW: Molecular basis for HLA-DQ associations with IDDM. Diabetes 1998;47:1177-1184 3. Sanjeevi CB, DeWeese C, Landin-Olsson M, Kockum I, Dahlquist G, Lernmark A, Lybrand TP: Analysis of critical residues of HLA-DQ6 molecules in insulin-dependent diabetes mellitus. Tissue Antigens 1997;50:61-65 4. Sanjeevi CB, Lybrand TP, Stevanovic S, Rammensee HG: Molecular modeling of eluted peptides from DQ6 molecules (DQB1*0602 and DQB1*0604) negatively and positively associated with type 1 diabetes. Annals of the New York Academy of Sciences 2002;958:317-320 5. Ettinger RA, Papadopoulos GK, Moustakas AK, Nepom GT, Kwok WW: Allelic variation in key peptide-binding pockets discriminates between closely related diabetes-protective and diabetes- susceptible HLA-DQB1*06 alleles. J Immunol 2006;176:1988-1998 6. Ettinger RA, Kwok WW: A peptide binding motif for HLA-DQA1*0102/DQB1*0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus. J Immunol 1998;160:2365-2373 7. Hu X, Deutsch AJ, Lenz TL, Onengut-Gumuscu S, Han B, Chen WM, Howson JM, Todd JA, de Bakker PI, Rich SS, Raychaudhuri S: Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nature genetics 2015; 8. Koeleman BP, Lie BA, Undlien DE, Dudbridge F, Thorsby E, De Vries RR, Cucca F, Roep BO, Giphart MJ, Todd JA: Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. Genes Immun 2004;5:381-388 9. van Lummel M, van Veelen PA, Zaldumbide A, de Ru A, Janssen GM, Moustakas AK, Papadopoulos GK, Drijfhout J, Roep BO, Koning F: The type 1 diabetes associated HLA-DQ8- trans dimer accomodates a unique peptide repertoire. JBiolChem 2011; 10. Eerligh P, van Lummel M, Zaldumbide A, Moustakas AK, Duinkerken G, Bondinas G, Koeleman BP, Papadopoulos GK, Roep BO: Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes. Genes and immunity 2011;12:415-427 11. Cai R, Liu Z, Ren J, Ma C, Gao T, Zhou Y, Yang Q, Xue Y: GPS-MBA: computational analysis of MHC class II epitopes in type 1 diabetes. PloS one 2012;7:e33884 12. van Lummel M, van Veelen PA, de Ru AH, Janssen GM, Pool J, Laban S, Joosten AM, Nikolic T, Drijfhout JW, Mearin ML, Aanstoot HJ, Peakman M, Roep BO: Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR. J Immunol 2016;196:3253-3263

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13. van Lummel M, van Veelen PA, de Ru AH, Pool J, Nikolic T, Laban S, Joosten A, Drijfhout JW, Gomez-Tourino I, Arif S, Aanstoot HJ, Peakman M, Roep BO: Discovery of a Selective Islet Peptidome Presented by the Highest-Risk HLA-DQ8trans Molecule. Diabetes 2016;65:732-741 14. Unger WW, Laban S, Kleijwegt FS, van der Slik AR, Roep BO: Induction of Treg by monocyte- derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. EurJImmunol 2009;39:3147-3159 15. Blum JS, Wearsch PA, Cresswell P: Pathways of antigen processing. Annual review of immunology 2013;31:443-473 16. Di Lorenzo TP, Peakman M, Roep BO: Translational mini-review series on type 1 diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 2007;148:1-16 17. Yang J, Danke N, Roti M, Huston L, Greenbaum C, Pihoker C, James E, Kwok WW: CD4+ T cells from type 1 diabetic and healthy subjects exhibit different thresholds of activation to a naturally processed proinsulin epitope. J Autoimmun 2008;31:30-41 18. Stadinski B, Kappler J, Eisenbarth GS: Molecular targeting of islet autoantigens. Immunity 2010;32:446-456 19. Tan S, Li Y, Xia J, Jin CH, Hu Z, Duinkerken G, Li Y, Khosravi Maharlooei M, Chavez E, Nauman G, Danzl N, Nakayama M, Roep BO, Sykes M, Yang YG: Type 1 diabetes induction in humanized mice. Proc Natl Acad Sci U S A 2017;114:10954-10959 20. Concannon P, Rich SS, Nepom GT: Genetics of type 1A diabetes. NEnglJMed 2009;360:1646- 1654 21. Sanjeevi CB, Sedimbi SK, Landin-Olsson M, Kockum I, Lernmark A: Risk conferred by HLA- DR and DQ for type 1 diabetes in 0-35-year age group in Sweden. AnnNYAcadSci 2008;1150:106-111 22. Burlingham WJ, Benichou G: Bidirectional alloreactivity: A proposed microchimerism-based solution to the NIMA paradox. Chimerism 2012;3:29-36 23. Hirayama M, Azuma E, Komada Y: Tolerogenic effect of non-inherited maternal antigens in hematopoietic stem cell transplantation. Front Immunol 2012;3:135 24. Matsuoka K, Ichinohe T, Hashimoto D, Asakura S, Tanimoto M, Teshima T: Fetal tolerance to maternal antigens improves the outcome of allogeneic bone marrow transplantation by a CD4+ CD25+ T-cell-dependent mechanism. Blood 2006;107:404-409 25. Kockum I, Wassmuth R, Holmberg E, Michelsen B, Lernmark A: Inheritance of MHC class II genes in IDDM studied in population-based affected and control families. Diabetologia 1994;37:1105-1112 26. Feitsma AL, van der Helm-van Mil AH, Huizinga TW, De Vries RR, Toes RE: Protection against rheumatoid arthritis by HLA: nature and nurture. AnnRheumDis 2008;67 Suppl 3:iii61-iii63 27. Feitsma AL, Worthington J, van der Helm-van Mil AH, Plant D, Thomson W, Ursum J, van SD, van der Horst-Bruinsma IE, van Rood JJ, Huizinga TW, Toes RE, De Vries RR: Protective effect

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of noninherited maternal HLA-DR antigens on rheumatoid arthritis development. ProcNatlAcadSciUSA 2007;104:19966-19970 28. Zanone MM, Favaro E, Miceli I, Grassi G, Camussi E, Caorsi C, Amoroso A, Giovarelli M, Perin PC, Camussi G: Human mesenchymal stem cells modulate cellular immune response to islet antigen glutamic acid decarboxylase in type 1 diabetes. JClinEndocrinolMetab 2010;95:3788- 3797 29. Ezquer F, Ezquer M, Contador D, Ricca M, Simon V, Conget P: The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells 2012;30:1664-1674 30. Madec AM, Mallone R, Afonso G, Abou ME, Mesnier A, Eljaafari A, Thivolet C: Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 2009;52:1391-1399 31. Urban VS, Kiss J, Kovacs J, Gocza E, Vas V, Monostori E, Uher F: Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 2008;26:244-253 32. Yeung TY, Seeberger KL, Kin T, Adesida A, Jomha N, Shapiro AM, Korbutt GS: Human mesenchymal stem cells protect human islets from pro-inflammatory cytokines. PLoSOne 2012;7:e38189

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TABLE 1. Alignments and core predictions of length variants of DQ6 eluted peptides. Overview of peptide alignments and binding core identifications of length variants eluted from DQ6 expressing EBV-BLCL. Anchors are in bold.

HLA-DQ6 123456789 AGHTSGAAMWPGTDVK YPFDFQGARIITGQEEG GPGAAVVAGAVVGTLVG AVPVMVPAQSQAGSLV DNVLMSGVKNNVGRGIN SQLIMQAEAEAASVR ELQEPAELVESDG TDQVQAEAKESGPT TGETYTCVVAHEALPNR GALTSGVHTFPAVLQ TDTDQACSIRDPNSG KSGNTASLTISGLQ VLHVWGVTTEKSKE EPAEVTATVLASRDD DSNEFSVIADPRG

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TABLE 2. In silico binding predictions of natural islet peptides eluted from DQ6

expressed on DQ6/8 heterozygous dendritic cells. By employing the peptide-binding motifs of protective DQ6 and susceptible DQ8, natural peptides derived from PPI and IA-2 eluted from autoantigen-pulsed DQ6/8 expressing DC were in silico validated as DQ6-binding natural

islet peptides (anchor residues in bold; minimal binding registers underlined). No prediction

hits were observed for DQ8.

Observed Calculated Corresponding Residues m/z m/z protein sequence PPI 541.29 1080.56 14-22 LALWGPDPA 910.48 1818.95 14-23 LALWGPDPAA 784.36 783.35 14-24 LALWGPDPAAA 713.32 712.31 14-29 LALWGPDPAAAFVNQH IA-2 core 1 620.34 1239.67 374-386 NPGGVVNVGADIK 666.68 1998.03 374-393 NPGGVVNVGADIKKTMEGPV core 2 804.08 2410.21 491-513 EILAEHVHMSSGSFINISVVGPA 1141.09 2281.16 492-513 ILAEHVHMSSGSFINISVVGPA 723.37 2168.08 493-513 LAEHVHMSSGSFINISVVGPA 685.67 2055.00 494-513 AEHVHMSSGSFINISVVGPA 661.99 1983.96 495-513 EHVHMSSGSFINISVVGPA 843.91 1686.83 496-511 HVHMSSGSFINISVVG 775.39 1549.77 497-511 VHMSSGSFINISVVG core 3 1028.57 2056.13 534-553 AGLVKSELEAQTGLQILQTG 1239.67 2478.33 543-566 AQTGLQILQTGVGQREEAAAVLPQ core 4 1053.67 1053.67 582-593 VALAGVAGLLVA

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LEGENDS

Figure 1. Frequency of the amino acids at anchor and non-anchor positions within the

binding core of protective and susceptible HLA-DQ. After performing core analysis of the

eluted unique peptides from HLA-DQ6 expressing EBV-BLCL, the distribution of amino acids

at both anchor (p1, p4, p6, p7, p9) and non-anchor positions (p2, p3, p5, p8) for protective DQ6

and susceptible DQ2 and DQ8 was calculated and compared to the amino acid frequency of the

human proteome. The figure shows the heatmap results of an iceLogo analysis for each HLA-

DQ molecule. Heatmaps for the susceptible HLA-DQ2 and -DQ8 molecules, already reported

by us and others, have been added to the DQ6 heatmap to demonstrate the differences between

protective and susceptible T1D HLA-DQ molecules. Increased or decreased amino acid

frequencies are shown in a gradient of respectively green or red shades.

Figure 2. Binding of InsB6-23 to HLA-DQ6, -DQ8 and -DQ6/8. Binding of InsB6-23,

harboring to distinct but partially overlapping binding6-23 cores for HLA-DQ6 and -DQ8, was

tested to HLA-DQ6, -DQ8 or -DQ6/8 in cell-free competitive HLA-DQ/peptide binding assays.

Indicator peptides were used at a fixed concentration (0.6µM) and were specific for either DQ6

(ZAAVKGSSLHVGAA) or DQ8 (ZEEPRAPWIEQEGPEYWDQE, i.e. EPRAP). InsB6-23

was tested in a concentration range (0-300µM). For DQ6/8 binding assays, binding of InsB6-

23 was tested in the presence of the DQ8-specific or the DQ6-specific reporter peptide. EC50

(half maximal effective concentration) values (in µM) were calculated on the basis of

competition between a biotinylated indicator peptide and the tested natural processed and

presented peptides (NPPP). Data represent mean ± SEM (n=3). Shown on the x-axes is 1/EC50,

thereby illustrating that large bars represent better binding.

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Figure 3. Elution of natural processed and presented islet peptides from DQ6/8 heterozygous dendritic cells. HLA-DQ6/8 heterozygous DC were pulsed for six hours with the islet-autoantigens PPI, IA-2 and GAD65 after which the DC were matured for 24 hours with LPS in the continuous presence of the three islet-autoantigens. After cell lysis, HLA_DQ8 was purified using IVD12 (HLA-DQ8-capturing antibody) and HLA-DQ6 using SPV-L3 (pan-

DQ) and peptides were acid eluted and analysed by mass spectrometry. Nested sets of peptides, covering one or more core-regions of PPI and IA-2 were identified.

24 Page 25 of 49 Diabetes

FIGURE 1

Diabetes Page 26 of 49

FIGURE 2

10

M) 1 µ ( 50

1/EC 0.1

0.01 /6 /8 8/8 6 6 Q D DQ6/8 DQ DQ

DQ6 DQ8 competition competition

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FIGURE 3

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SUPPLEMENTAL TABLE 1. Unique eluted peptides from HLA-DQ6.2 expressing EBV-BLCL. HLA-DQ6.2 expressing cells (total 7.5*109) were eluted and eluted peptides were detected employing mass spectrometry as described in Research design and methods. A total of 1156 unique peptides (ordered per protein) are shown with Best Mascot Ion scores > 45. The peptide sequences of these peptides have been used to obtain the peptide binding motif of HLA-DQ6.2 by molecular modelling as described in research design and methods.

Protein Mascot Peptide Mascot Protein name accession Peptide sequence Identity Start Stop Ion score number identification score AARS Alanyl-tRNA synthetase, cytoplasmic IPI00027442 EALATAVIPQWQKDE 95.00% 62.4 40.7 800 814 ABCA3 ATP-binding cassette sub-family A member 3 IPI00017800 DPSDGIGALIEEERT 95.00% 99.2 39.1 883 897 ABCA3 ATP-binding cassette sub-family A member 3 IPI00017800 DPSDGIGALIEEER 95.00% 90.6 40.2 883 896 ABCB6 Isoform 4 of ATP-binding cassette sub-family B member 6, mitochondrial IPI00065486 NDEVEAAAQAAGIHD 95.00% 125 38.2 152 166 ABCB6 Isoform 4 of ATP-binding cassette sub-family B member 6, mitochondrial IPI00065486 DEVEAAAQAAGIHDA 95.00% 101 37.9 153 167 ABCB6 Isoform 4 of ATP-binding cassette sub-family B member 6, mitochondrial IPI00065486 GNDEVEAAAQAAGIHDA 95.00% 99.8 37.2 151 167 ABCB6 Isoform 4 of ATP-binding cassette sub-family B member 6, mitochondrial IPI00065486 NDEVEAAAQAAGIHDA 95.00% 97.4 38.4 152 167 ABCB6 Isoform 4 of ATP-binding cassette sub-family B member 6, mitochondrial IPI00065486 GNDEVEAAAQAAGIHD 95.00% 79.6 36.6 151 166 ACTB Actin, cytoplasmic 1 IPI00021439 NTVLSGGTTMYPGIADR 95.00% 141 40.5 296 312 ACTB Actin, cytoplasmic 1 IPI00021439 NTVLSGGTTMYPGIADRM 95.00% 140 39.8 296 313 ACTB Actin, cytoplasmic 1 IPI00021439 TVLSGGTTMYPGIADR 95.00% 140 40.6 297 312 ACTB Actin, cytoplasmic 1 IPI00021439 TVLSGGTTMYPGIADRM 95.00% 137 40.3 297 313 ACTB Actin, cytoplasmic 1 IPI00021439 TVLSGGTTMYPGIADRMQ 95.00% 130 40.4 297 314 ACTB Actin, cytoplasmic 1 IPI00021439 NTVLSGGTTMYPGIADRMQ 95.00% 118 40.1 296 314 ACTB Actin, cytoplasmic 1 IPI00021439 YANTVLSGGTTMYPGIADR 95.00% 107 40 294 312 ACTB Actin, cytoplasmic 1 IPI00021439 LSGGTTMYPGIADR 95.00% 101 38.7 299 312 ACTB Actin, cytoplasmic 1 IPI00021439 VLSGGTTMYPGIADR 95.00% 97.6 39.3 298 312 ACTB Actin, cytoplasmic 1 IPI00021439 LSGGTTMYPGIADRM 95.00% 93.5 39.3 299 313 ACTB Actin, cytoplasmic 1 IPI00021439 NTVLSGGTTMYPGIAD 95.00% 88 39.2 296 311 ACTB Actin, cytoplasmic 1 IPI00021439 SGGTTMYPGIADR 95.00% 81.8 37.6 300 312 ACTB Actin, cytoplasmic 1 IPI00021439 LSGGTTMYPGIADRMQ 95.00% 53 38.7 299 314 ACTB Actin, cytoplasmic 1 IPI00021439 VLSGGTTMYPGIAD 95.00% 51.9 40.3 298 311 ACTB Actin, cytoplasmic 1 IPI00021439 ANTVLSGGTTMYPGIAD 95.00% 51.5 40.1 295 311 ACTB Actin, cytoplasmic 1 IPI00021439 DFEQEMATAASSSS 95.00% 103 31.5 222 235 ACTB Actin, cytoplasmic 1 IPI00021439 ATAASSSSLEKSYELPD 95.00% 66.4 39.2 228 244 ACTB Actin, cytoplasmic 1 IPI00021439 ATAASSSSLEKSYELPDG 95.00% 58.7 39.3 228 245 ACTB Actin, cytoplasmic 1 IPI00021439 DFEQEMATAASSSSLE 95.00% 52.4 34.2 222 237 ACTB Actin, cytoplasmic 1 IPI00021439 DSGDGVTHTVPIYEGYA 95.00% 57.1 38.1 154 170 ADAM10 ADAM 10 IPI00013897 KSLNTGIITVQNYG 95.00% 70.1 40.1 175 188 ADAM10 ADAM 10 IPI00013897 KYQMTGVEEVTQIPQ 95.00% 61.6 40.8 3 17 ADAM9 Isoform 1 of ADAM 9 IPI00440932 APRPYSKQVSYVIQAEGKEH 95.00% 57.8 41.7 58 77 AGRN Agrin IPI00374563 TEATQGLVLWSGKAT 95.00% 86 39.9 1899 1913 AGRN Agrin IPI00374563 TEATQGLVLWSGKATER 95.00% 75.2 40.8 1899 1915 AGRN Agrin IPI00374563 TEATQGLVLWSGKATE 95.00% 68.1 40.9 1899 1914 AGRN Agrin IPI00374563 APDFSKLARAAAVSSGFDGAIQ 95.00% 74.5 41 1768 1789 AGRN Agrin IPI00374563 VPEDQAAVALERTFVG 95.00% 86.5 40.6 1498 1513 AGRN Agrin IPI00374563 GVPEDQAAVALERTFVG 95.00% 61.3 40.8 1497 1513 AGRN Agrin IPI00374563 VPEDQAAVALERTFVGA 95.00% 50.7 40.6 1498 1514 ALB Uncharacterized protein ALB IPI00022434 LVTDLTK 95.00% 48.8 39 143 149 ALDOA Fructose-bisphosphate aldolase A IPI00465439 TPSGQAGAAASESL 95.00% 94.8 40.4 398 411 ALDOA Fructose-bisphosphate aldolase A IPI00465439 TPSGQAGAAASESLF 95.00% 69.5 40 398 412 ALDOA Fructose-bisphosphate aldolase A IPI00465439 TPSGQAGAAASESLFV 92.30% 46.8 39.7 398 413 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 EDVGSNKGAIIGLMVG 95.00% 67.8 41.5 674 689 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 EDVGSNKGAIIGLMVGGV 95.00% 65.4 40.8 674 691 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 AEDVGSNKGAIIGLMVGGV 95.00% 64.1 40.7 673 691 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 EDVGSNKGAIIGLMVGG 95.00% 63.9 41.3 674 690 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 DVGSNKGAIIGLMVGGV 95.00% 61 40.2 675 691 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 DVGSNKGAIIGLMVGGVV 95.00% 60 38.7 675 692 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 DVGSNKGAIIGLMVG 95.00% 51.2 39 675 689 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 AEDVGSNKGAIIGLMVG 94.80% 49.9 41.1 673 689 APP Isoform APP770 of Amyloid beta A4 protein (Fragment) IPI00006608 DVGSNKGAIIGLMVGG 95.00% 48.1 39.1 675 690 APPL1 DCC-interacting protein 13-alpha IPI00015836 FLANIGTSVQNVR 95.00% 112 39.2 225 237 ARID1B Isoform 1 of AT-rich interactive domain-containing protein 1B IPI00015404 GAGAVAAAAAAAAAA 95.00% 83 38.6 335 349 ARL8B ADP-ribosylation factor-like protein 8B IPI00018871 GVNAIVYMIDAADRE 95.00% 82.5 40 88 102 ARL8B ADP-ribosylation factor-like protein 8B IPI00018871 RGVNAIVYMIDAADREK 95.00% 63.1 40.6 87 103 ATP11B Probable phospholipid-transporting ATPase IF IPI00240793 DGANDVSMIQEAHVG 95.00% 99 36.3 405 419 ATP1A1 Isoform Long of Sodium/potassium-transporting ATPase subunit alpha-1IPI00006482 IISANGCKVDNSSLT 95.00% 73.2 41.5 204 218 ATP1A1 Isoform Long of Sodium/potassium-transporting ATPase subunit alpha-1IPI00006482 IISANGCKVDNSSLTG 95.00% 51.9 40.6 204 219 ATP1A1 Isoform Long of Sodium/potassium-transporting ATPase subunit alpha-1IPI00006482 LDDNFASIVTGVEEG 95.00% 60 39.5 750 764 ATP1A1 Isoform Long of Sodium/potassium-transporting ATPase subunit alpha-1IPI00006482 LDDNFASIVTGVE 95.00% 57.2 40.9 750 762 ATP1A1 Isoform Long of Sodium/potassium-transporting ATPase subunit alpha-1IPI00006482 NPRDAKACVVHGSDL 95.00% 57 39.7 655 669 ATP1A1 Isoform Long of Sodium/potassium-transporting ATPase subunit alpha-1IPI00006482 NPRDAKACVVHGSDLK 90.70% 48.5 40.8 655 670 Page 29 of 49 Diabetes

ATP2B1 Isoform D of Plasma membrane calcium-transporting ATPase 1 IPI00021695 DPLLLSGTHVMEGSGRM 89.40% 46.5 40.6 257 273 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 ITGDSQETAVAIASR 95.00% 114 40.8 569 583 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 ITGDSQETAVAIASRLG 95.00% 114 40.5 569 585 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 TGDSQETAVAIASRLG 95.00% 78 40.1 570 585 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 DGVNDAVALKAADIG 95.00% 91.9 40.8 644 658 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 GKPTEGALIALAMK 95.00% 85 35.3 423 436 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 KPTEGALIALAMK 95.00% 77.2 34.6 424 436 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 YEQVIKYCTTYQSKG 95.00% 65.4 40.2 483 497 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 GDGVNDAVALKAADIG 95.00% 57.3 40.6 643 658 ATP2C1 Isoform 2 of Calcium-transporting ATPase type 2C member 1 IPI00220473 EQVIKYCTTYQSKG 95.00% 53.5 39.6 484 497 ATP5A1 ATP synthase subunit alpha, mitochondrial IPI00440493 EPDNVGVVVFGNDK 95.00% 112 39.1 110 123 ATP6AP1 Vacuolar ATP synthase subunit S1 IPI00784119 NKQDSAFSNLENALD 95.00% 87.9 38.7 111 125 ATP6AP1 Vacuolar ATP synthase subunit S1 IPI00784119 VPYTAALTAVRPSRVA 91.90% 46.8 37.2 213 228 ATP7A Isoform 4 of Copper-transporting ATPase 1 IPI00028610 LSDTNEPLVVIAQPSSE 95.00% 90.1 40.8 444 460 ATP7A Isoform 4 of Copper-transporting ATPase 1 IPI00028610 DTNEPLVVIAQPSS 95.00% 59.1 40.7 446 459 ATP7A Isoform 4 of Copper-transporting ATPase 1 IPI00028610 SDTNEPLVVIAQPSSE 95.00% 52.1 40.3 445 460 ATP7A Isoform 4 of Copper-transporting ATPase 1 IPI00028610 KPGSTVIAGSINQNGSL 95.00% 57 40.7 806 822 ATP8A1 Isoform Long of Probable phospholipid-transporting ATPase IA IPI00032402 DGANDVSMIQTAHVG 95.00% 90.1 37.5 793 807 ATP8A1 Isoform Long of Probable phospholipid-transporting ATPase IA IPI00032402 NGIVSQSEVIRAYDTT 95.00% 77.5 39.8 1134 1149 ATP8A1 Isoform Long of Probable phospholipid-transporting ATPase IA IPI00032402 GIVSQSEVIRAYDTTKQRP 95.00% 63 41 1135 1153 ATP8A1 Isoform Long of Probable phospholipid-transporting ATPase IA IPI00032402 ENDFALIIDGKT 95.00% 76.6 41.6 729 740 ATP8A1 Isoform Long of Probable phospholipid-transporting ATPase IA IPI00032402 KENDFALIIDGKT 95.00% 71.4 40.6 728 740 ATP8A1 Isoform Long of Probable phospholipid-transporting ATPase IA IPI00032402 RKENDFALIIDGKT 93.50% 52.3 39.9 727 740 B2M B2M protein IPI00796379 TPTEKDEYACRVNHVT 95.00% 53.3 39.2 91 106 B4GALT1 Isoform Long of Beta-1,4-galactosyltransferase 1 IPI00215767 TPLQGGSNSAAAIGQSSGELR 95.00% 144 40.6 45 65 B4GALT1 Isoform Long of Beta-1,4-galactosyltransferase 1 IPI00215767 GGSNSAAAIGQSSGEL 95.00% 118 39.1 49 64 B4GALT1 Isoform Long of Beta-1,4-galactosyltransferase 1 IPI00215767 TPLQGGSNSAAAIGQSSGEL 95.00% 109 40.2 45 64 B4GALT1 Isoform Long of Beta-1,4-galactosyltransferase 1 IPI00215767 GGSNSAAAIGQSSGELR 95.00% 90.4 39.9 49 65 B4GALT1 Isoform Long of Beta-1,4-galactosyltransferase 1 IPI00215767 TPLQGGSNSAAAIGQS 95.00% 80.4 39.6 45 60 B4GALT1 Isoform Long of Beta-1,4-galactosyltransferase 1 IPI00215767 GGSNSAAAIGQSSG 95.00% 74.5 37.1 49 62 B4GALT1 Isoform Long of Beta-1,4-galactosyltransferase 1 IPI00215767 TPLQGGSNSAAAIGQ 95.00% 54.7 39.7 45 59 B4GALT5 Beta-1,4-galactosyltransferase 5 IPI00011656 DNVRTIGAQVYEQV 95.00% 85.8 40.6 55 68 B4GALT5 Beta-1,4-galactosyltransferase 5 IPI00011656 DNVRTIGAQVYEQ 95.00% 82.9 40.1 55 67 B4GALT5 Beta-1,4-galactosyltransferase 5 IPI00011656 DNVRTIGAQVYEQVL 95.00% 78.2 40.5 55 69 B4GALT5 Beta-1,4-galactosyltransferase 5 IPI00011656 DNVRTIGAQVYEQVLR 95.00% 66 40.3 55 70 BIRC6 baculoviral IAP repeat-containing 6 IPI00299635 QSPSANVL 95.00% 45.3 42.3 4202 4209 BLMH Bleomycin hydrolase IPI00219575 AQNVGTTHDL 95.00% 47.7 38.2 107 116 BMPR2 Bone morphogenetic protein receptor type-2 IPI00783156 SVNSHAATTQYANGTV 95.00% 61.4 38.6 815 830 BST2 Bone marrow stromal antigen 2 IPI00026241 QQELTEAQKGFQDVE 95.00% 70.5 39.4 71 85 BST2 Bone marrow stromal antigen 2 IPI00026241 LQQELTEAQKGFQDVE 95.00% 66.8 40.9 70 85 BST2 Bone marrow stromal antigen 2 IPI00026241 LLQQELTEAQKGFQDVE 95.00% 66.7 41 69 85 BTN3A2 Butyrophilin subfamily 3 member A2 IPI00099583 EVAASVIMRGGSGEG 95.00% 73.3 40.6 203 217 C14orf56 similar to FLJ00035 protein IPI00888501 KEAGNGVN 95.00% 56.7 41.5 109 116 C19orf28 Isoform 2 of Uncharacterized MFS-type transporter C19orf28 IPI00166640 GPHTNSGAFVYGSMS 95.00% 49.9 35.2 386 400 C1orf38 Isoform 2 of Induced by contact to basement membrane 1 protein IPI00003922 LEELVSATTQSSKQ 95.00% 105 40.7 93 106 C21orf67 Isoform A of Uncharacterized protein C21orf67 IPI00067917 VENPSPI 95.00% 56.5 39.5 10 16 C3orf52 TPA-induced transmembrane protein IPI00303046 TPLNGADKVFPSLD 95.00% 72.7 40.1 26 39 C6orf72 Uncharacterized protein C6orf72 IPI00026031 QVYVNDLPVNSGVTR 95.00% 71.2 40.7 71 85 CADM1 Isoform 1 of Cell adhesion molecule 1 IPI00003813 VPPRNLMIDIQKDTAVE 94.50% 54.6 39.7 142 158 CADM1 Isoform 1 of Cell adhesion molecule 1 IPI00003813 VPPRNLMIDIQKDTAVEG 93.40% 52.3 40.1 142 159 CALCOCO2 Calcium-binding and coiled-coil domain-containing protein 2 IPI00743360 LPIDLNNKSAKQQEVQ 95.00% 74.5 38.9 77 92 CALCOCO2 Calcium-binding and coiled-coil domain-containing protein 2 IPI00743360 MKQNETTAMKKQQELMD 95.00% 55.2 38.9 289 305 CALCOCO2 Calcium-binding and coiled-coil domain-containing protein 2 IPI00743360 VDEDGVVRGASIPFQFRPEN 92.20% 51.7 41.7 110 129 CALCOCO2 Calcium-binding and coiled-coil domain-containing protein 2 IPI00743360 VDEDGVVRGASIPFQFRPE 92.10% 51.3 41.5 110 128 CALCOCO2 Calcium-binding and coiled-coil domain-containing protein 2 IPI00743360 VDEDGVVRGASIPFQ 95.00% 49.5 40.2 110 124 CALCOCO2 Calcium-binding and coiled-coil domain-containing protein 2 IPI00743360 EDGVVRGASIPFQFRPE 90.70% 48.7 41.1 112 128 CALM3;CALM2;CALM1 Calmodulin IPI00075248 VNYEEFVQMMTAK 95.00% 95.1 38.6 140 152 CALM3;CALM2;CALM1 Calmodulin IPI00075248 GYISAAELRHVMT 95.00% 77.4 39.6 102 114 CALM3;CALM2;CALM1 Calmodulin IPI00075248 GYISAAELRHVMTN 95.00% 73 40.2 102 115 CALM3;CALM2;CALM1 Calmodulin IPI00075248 DGNGYISAAELRHVMTN 95.00% 68.9 39.5 99 115 CALM3;CALM2;CALM1 Calmodulin IPI00075248 NGYISAAELRHV 95.00% 66.2 40.1 101 112 CALM3;CALM2;CALM1 Calmodulin IPI00075248 DGNGYISAAELRHVMT 95.00% 65.3 40.2 99 114 CALM3;CALM2;CALM1 Calmodulin IPI00075248 NGYISAAELRHVMTN 95.00% 63.5 39.8 101 115 CALM3;CALM2;CALM1 Calmodulin IPI00075248 DKDGNGYISAAELRHVMTN 95.00% 60.2 39.9 97 115 CALM3;CALM2;CALM1 Calmodulin IPI00075248 DGNGYISAAELRHVM 95.00% 57.4 39.2 99 113 CALM3;CALM2;CALM1 Calmodulin IPI00075248 DKDGDGTITTKELGTVMRSLG 94.80% 56.8 41.2 21 41 CALML5 Calmodulin-like protein 5 IPI00021536 FSAVDTDGNGTIN 95.00% 95.7 37.6 17 29 CALML5 Calmodulin-like protein 5 IPI00021536 SAVDTDGNGTIN 95.00% 76.2 36.7 18 29 CAPG gelsolin-like capping protein IPI00848090 APNTQVEILPQGHE 95.00% 79.4 41.1 323 336 CAPG gelsolin-like capping protein IPI00848090 TGQMNLTKVADSSPF 95.00% 57.3 40.4 258 272 Diabetes Page 30 of 49

CAPG Macrophage-capping protein IPI00027341 TGQMNLTKVADSSPF 95.00% 57.3 40.4 258 272 CAPG Macrophage-capping protein IPI00027341 APNTQVEILPQGRE 95.00% 74.9 39.1 323 336 CAPG Macrophage-capping protein IPI00027341 APNTQVEILPQGRES 94.80% 49.1 40.3 323 337 CCAR1 Cell division cycle and apoptosis regulator protein 1 IPI00217357 LQQQAAAAAAA 95.00% 59.4 39.4 69 79 CCDC50 Isoform 2 of Coiled-coil domain-containing protein 50 IPI00217059 QVDMRAAQVAQDEEIA 95.00% 65.5 39.1 323 338 CCR7 C-C chemokine receptor type 7 IPI00027687 NITSSTCELSKQ 95.00% 85 38.3 292 303 CCT2 T-complex protein 1 subunit beta IPI00297779 EGNTTAGLDMREGTIGDM 95.00% 76.9 35.8 471 488 CCT8 59 kDa protein IPI00302925 EDGAISTIVLRGSTDN 95.00% 88.3 40.7 368 383 CCT8 59 kDa protein IPI00302925 DGAISTIVLRGSTDNL 95.00% 86.4 40 369 384 CCT8 59 kDa protein IPI00302925 DGAISTIVLRGSTDN 95.00% 84.2 40.8 369 383 CD22 Isoform CD22-alpha of B-cell receptor CD22 IPI00218390 QWLLEGVPMRQAAVT 95.00% 73 40.5 175 189 CD22 Isoform CD22-alpha of B-cell receptor CD22 IPI00218390 QWLLEGVPMRQAA 95.00% 51.6 39.3 175 187 CD300A Isoform 2 of CMRF35-like molecule 8 IPI00054095 SPREELHYASVVFDSNTN 95.00% 70.3 39.1 111 128 CD320 CD320 antigen IPI00641251 YGVIAAAAVLSAS 95.00% 80.8 40.5 187 199 CD40 Isoform I of Tumor necrosis factor receptor superfamily member 5 IPI00018282 APVQETLHGCQPVTQEDGKE 95.00% 72.9 39.2 249 268 CD40 Isoform I of Tumor necrosis factor receptor superfamily member 5 IPI00018282 APVQETLHGCQPVTQEDG 95.00% 62.2 38.7 249 266 CD44 Isoform 12 of CD44 antigen IPI00297160 DETRNLQNVDMKIGV 95.00% 60.7 40.7 677 691 CD44 Isoform 12 of CD44 antigen IPI00297160 ADETRNLQNVDMKIGV 94.30% 54.8 40.4 676 691 CD47 Isoform OA3-293 of Leukocyte surface antigen CD47 IPI00216514 VPTDFSSAKIEVSQ 95.00% 83.2 41.2 77 90 CD47 Isoform OA3-293 of Leukocyte surface antigen CD47 IPI00216514 VPTDFSSAKIEVSQL 95.00% 61.6 40.9 77 91 CD55 Decay-accelerating factor splicing variant 4 IPI00152418 LISGSSVQWSDPLPE 95.00% 75.1 40.8 205 219 CD55 Decay-accelerating factor splicing variant 4 IPI00152418 ISGSSVQWSDPLPE 95.00% 51.7 39.2 206 219 CD69 Early activation antigen CD69 IPI00014854 TSAQNACSEHGATL 95.00% 49.2 35.4 107 120 CD70 CD70 antigen IPI00031713 IQRFAQAQQQLPLE 91.60% 46.8 40 38 51 CD79A Isoform Long of B-cell antigen receptor complex-associated protein alphaIPI00008473 GLNLDDCSMYEDISRG 95.00% 85.2 33.9 152 167 CD80 T-lymphocyte activation antigen CD80 IPI00015914 VEELAQTRIYWQKE 94.60% 55.7 40.5 56 69 CD84 Isoform 3 of SLAM family member 5 IPI00022039 YDEILQSKVLPSKEEPV 90.10% 47.5 40.7 165 181 CD97 Isoform 2 of CD97 antigen IPI00299412 APPVRHLIATQLLSNLED 90.60% 46.9 39.4 318 335 CDC42SE2 CDC42 small effector protein 2 IPI00024973 SGMNSVSSIQNQMQ 95.00% 58.9 36.3 48 61 CDSN cDNA FLJ78714, highly similar to Homo sapiens corneodesmosin, mRNA IPI00646774 GILNPSQPGQSSSSSQT 95.00% 66.2 39.3 185 201 CHL1 Isoform 2 of Neural cell adhesion molecule L1-like protein IPI00299059 IPSSVQQVPTIIKQSKVQ 92.30% 45.2 35.1 13 30 CLCN7 Putative chloride channel protein 7 IPI00020524 GPMIHSGSVIAAGISQG 95.00% 59.5 40.5 201 217 CMIP Isoform 1 of C-Maf-inducing protein IPI00028438 IDNNDTQLQIIS 94.00% 49.5 41.3 454 465 CMIP Isoform 1 of C-Maf-inducing protein IPI00028438 IIDNNDTQLQIIS 85.30% 45.7 41.3 453 465 COCH Cochlin IPI00012386 EISDIGAKIAAVQ 95.00% 82.7 41.1 249 261 COCH Cochlin IPI00012386 EISDIGAKIAAVQFT 90.40% 46.7 40.5 249 263 COCH Cochlin IPI00012386 STKENVLAVIRNIR 92.90% 45.9 34.6 276 289 CPD Carboxypeptidase D IPI00027078 AENGLESLMLRSSSN 95.00% 80 40.2 911 925 CPD Carboxypeptidase D IPI00027078 AENGLESLMLRSSSNL 95.00% 67.6 40.7 911 926 CPD Carboxypeptidase D IPI00027078 SGNLHGGSVVASYPFDD 95.00% 64.8 37.4 253 269 CPD Carboxypeptidase D IPI00027078 SGNLHGGSVVASYPFD 95.00% 55 39.1 253 268 CR2 Isoform B of Complement receptor type 2 IPI00216985 TPIAVGTVIR 95.00% 84.5 36.9 39 48 CR2 Isoform B of Complement receptor type 2 IPI00216985 TPIAVGTVIRYS 95.00% 81.2 39 39 50 CSTF2 Isoform 1 of Cleavage stimulation factor 64 kDa subunit IPI00013256 ATEEQLK 95.00% 56 44.3 27 33 CTNND1 Isoform 1AB of Catenin delta-1 IPI00182469 ASILASVKEQEAQFE 95.00% 83.9 40.9 10 24 CTSA Lysosomal protective protein IPI00021794 KDPENSPVVLWLNGGPG 95.00% 81.8 40.8 71 87 CTSD Cathepsin D IPI00011229 AIVDTGTSLMVGPVD 95.00% 52.2 41.1 163 177 CTSH Cathepsin H IPI00297487 GALESAIAIATGKM 95.00% 98.8 39.8 148 161 CTSH Cathepsin H IPI00297487 TGALESAIAIATGKM 95.00% 98.4 39.5 147 161 CTSH Cathepsin H IPI00297487 TTGALESAIAIATGKM 95.00% 94.7 41.3 146 161 CTSH Cathepsin H IPI00297487 GALESAIAIATGKMLS 95.00% 85.8 41 148 163 CTSH Cathepsin H IPI00297487 GALESAIAIATGKML 95.00% 79.5 38.5 148 162 CTSH Cathepsin H IPI00297487 TGALESAIAIATGKML 95.00% 78.7 40 147 162 CTSH Cathepsin H IPI00297487 TPDKVNHAVLAVGYGEK 95.00% 65.2 40 275 291 CTSH Cathepsin H IPI00297487 TPDKVNHAVLAVGYGEKN 95.00% 64.2 40.5 275 292 CTSH Cathepsin H IPI00297487 TPDKVNHAVLAVGYGEKNG 95.00% 57.5 40.5 275 293 CTSH Cathepsin H IPI00297487 GPQWGMNGYFLIERGKNM 95.00% 59.5 39.8 304 321 CTSH Cathepsin H IPI00297487 WGMNGYFLIERGKNM 94.40% 53.8 39.2 307 321 CTSH Cathepsin H IPI00297487 GPQWGMNGYFLIERGKN 93.60% 53.6 40.9 304 320 CTSS Cathepsin S IPI00299150 QNVNHGVLVVGYGDL 95.00% 74.1 39 274 288 CTSS Cathepsin S IPI00299150 NVNHGVLVVGYGDL 95.00% 52.3 39.5 275 288 CTSS Cathepsin S IPI00299150 IDNKGIDSDASYPY 95.00% 55 38.8 193 206 CTSS Cathepsin S IPI00299150 LPYGREDVLKEAVANKGPVS 91.80% 49.3 39.9 230 249 CTSZ Cathepsin Z IPI00002745 VDGVNYASITRNQHIPQ 93.20% 52.9 41 71 87 CTSZ Cathepsin Z IPI00002745 VDGVNYASITRNQH 91.80% 49 39.6 71 84 DAAM1 Isoform 1 of Disheveled-associated activator of morphogenesis 1 IPI00337800 IDQLNSMAARKSLL 95.00% 54.8 37.6 107 120 DAG1 Dystroglycan IPI00028911 VQFNSNSQLMYGLPDSS 95.00% 64.6 37.9 552 568 DCD Dermcidin IPI00027547 PGLARQ 95.00% 50.7 39.6 49 54 DDX6 Probable ATP-dependent RNA helicase DDX6 IPI00030320 DNIQAMVIVPTRE 95.00% 57.7 38.5 163 175 DHCR24 24-dehydrocholesterol reductase IPI00016703 AVIMTGVMTDEAEPS 95.00% 77.6 38.2 277 291 Page 31 of 49 Diabetes

DHCR24 24-dehydrocholesterol reductase IPI00016703 GGLIMGTGIESSSHK 95.00% 64.7 40.3 165 179 DHRS7 Isoform 1 of Dehydrogenase/reductase SDR family member 7 IPI00006957 DILVNNGGMSQRSL 95.00% 72 38.8 133 146 DNAJC5 Isoform 1 of DnaJ homolog subfamily C member 5 IPI00402231 DEREATDTPIVIQPASAT 95.00% 84.6 40.4 162 179 DNAJC5 Isoform 1 of DnaJ homolog subfamily C member 5 IPI00402231 EATDTPIVIQPASAT 95.00% 73.4 40.9 165 179 DNAJC5 Isoform 1 of DnaJ homolog subfamily C member 5 IPI00402231 EATDTPIVIQPASA 95.00% 50.7 40.7 165 178 DSP Isoform DPI of Desmoplakin IPI00013933 SEILSDPSDDTKG 95.00% 76.1 38.5 1802 1814 DSP Isoform DPI of Desmoplakin IPI00013933 ILSDPSDDTKG 95.00% 59.9 41.1 1804 1814 DSP Isoform DPI of Desmoplakin IPI00013933 IVDPVSNLR 95.00% 53.1 39.3 1701 1709 EEF1A1 Elongation factor 1-alpha IPI00025447 VIILNHPGQISAGYA 95.00% 70.8 40 344 358 EEF1A1 Elongation factor 1-alpha IPI00025447 IILNHPGQISAGYA 95.00% 70 40.5 345 358 EEF1A1 Elongation factor 1-alpha IPI00025447 VIILNHPGQISAGYAPV 95.00% 66.3 39.1 344 360 EEF1A1 Elongation factor 1-alpha IPI00025447 VIILNHPGQISAGYAP 95.00% 55 37.5 344 359 EEF1A1 Elongation factor 1-alpha IPI00025447 IILNHPGQISAGYAPV 95.00% 54.3 37.1 345 360 EEF1A1 Elongation factor 1-alpha IPI00025447 IILNHPGQISAGYAP 94.20% 48.6 40.3 345 359 EEF1A1 Elongation factor 1-alpha IPI00025447 KDGNASGTTLLEALD 95.00% 57.4 41.1 219 233 EEF1A1 Elongation factor 1-alpha IPI00025447 DGNASGTTLLEALD 89.90% 46.7 40.7 220 233 EFHD2 EF-hand domain-containing protein D2 IPI00060181 TPEQPGLNGAAAAAAGAPDEA 95.00% 79.2 39.4 24 44 EFHD2 EF-hand domain-containing protein D2 IPI00060181 QPGLNGAAAAAAGAPD 95.00% 49.5 39.3 27 42 EHD4 EH domain-containing protein 4 IPI00005578 SDEFSEAIKAFRGQDDK 90.10% 46.7 39.9 200 216 EIF4B Eukaryotic translation initiation factor 4B IPI00012079 SPTSGGGKVAPAQPS 95.00% 70.1 39.6 504 518 EIF6 Eukaryotic translation initiation factor 6 IPI00010105 GTVNRGSEVIAAGMV 95.00% 55.1 41 165 179 ENG Isoform Long of Endoglin IPI00017567 EPGQQSFVQVRVSPSVS 95.00% 71.1 40.6 468 484 ENG Isoform Long of Endoglin IPI00017567 EPGQQSFVQVRVSPS 95.00% 69.3 40.9 468 482 ENG Isoform Long of Endoglin IPI00017567 EPGQQSFVQVRVSPSV 95.00% 60.8 41 468 483 ENG Isoform Long of Endoglin IPI00017567 DANHNMQIWTTGEYS 95.00% 62.2 33.5 264 278 ENG Isoform Long of Endoglin IPI00017567 GPEGGTVELIQGRAAKGN 95.00% 56 39.1 498 515 ENG Isoform Long of Endoglin IPI00017567 GPEGGTVELIQGRAAKG 94.70% 54 38.6 498 514 ENG Isoform Long of Endoglin IPI00017567 IDANHNMQIWTTGEY 95.00% 52.9 36.7 263 277 ENG Isoform Long of Endoglin IPI00017567 IDANHNMQIWTTGEYS 95.00% 51.5 36.6 263 278 ENG Isoform Long of Endoglin IPI00017567 LIDANHNMQIWTTGEY 95.00% 50.3 39 262 277 ENG Isoform Long of Endoglin IPI00017567 IDANHNMQIWTTGE 95.00% 48.4 37.3 263 276 ENO1 Isoform alpha-enolase of Alpha-enolase IPI00465248 TDKVVIGMDVAASE 95.00% 87.8 40.4 144 157 ENO1 Isoform alpha-enolase of Alpha-enolase IPI00465248 TDKVVIGMDVAASEFF 95.00% 74.8 40.5 144 159 ENO1 Isoform alpha-enolase of Alpha-enolase IPI00465248 TDKVVIGMDVAASEF 95.00% 71.9 39.1 144 158 ENPP5 Ectonucleotide pyrophosphatase/phosphodiesterase family member 5 IPI00011994 AGHTSGAAMWPGTDVK 95.00% 89.4 38.8 130 145 ENTPD1 Isoform Placental I of Ectonucleoside triphosphate diphosphohydrolase IPI00220852 YPFDFQGARIITGQEEG 95.00% 83.4 39.9 159 175 ENTPD1 Isoform Placental I of Ectonucleoside triphosphate diphosphohydrolase IPI00220852 DFQGARIITGQEEG 95.00% 79.5 40.2 162 175 ENTPD1 Isoform Placental I of Ectonucleoside triphosphate diphosphohydrolase IPI00220852 YPFDFQGARIITGQEEGA 95.00% 67.6 39.7 159 176 ENTPD1 Isoform Placental I of Ectonucleoside triphosphate diphosphohydrolase IPI00220852 YPFDFQGARIITGQEE 95.00% 60.1 39.6 159 174 ENTPD1 Isoform Placental I of Ectonucleoside triphosphate diphosphohydrolase IPI00220852 DFQGARIITGQEEGA 95.00% 59.4 40.3 162 176 ESAM Endothelial cell-selective adhesion molecule IPI00303161 GPGAAVVAGAVVGTLVG 95.00% 49.8 37.2 244 260 ESAM Endothelial cell-selective adhesion molecule IPI00303161 AVPVMVPAQSQAGSLV 93.80% 48 39.9 375 390 F11R Junctional adhesion molecule A IPI00001754 SDTGEYSCEARNGYG 95.00% 64.5 28.7 205 219 F11R Junctional adhesion molecule A IPI00001754 DTGEYSCEARNGYG 95.00% 57.7 28 206 219 FAM38A family with sequence similarity 38, member A IPI00006093 DPGEREAGASLYQGLM 95.00% 67.5 38.7 1667 1682 FAM3C Protein FAM3C IPI00334282 DNVLMSGVKNNVGRGIN 95.00% 64.2 41.1 89 105 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 DQMAQKSQSTQISQELEE 95.00% 126 38.2 76 93 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 DQMAQKSQSTQISQELE 95.00% 98.1 39.4 76 92 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 MAQKSQSTQISQELEE 95.00% 97.4 39.6 78 93 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 DQMAQKSQSTQISQELEEL 95.00% 91.9 39.9 76 94 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 MAQKSQSTQISQELEEL 95.00% 88.2 40.6 78 94 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 GDQMAQKSQSTQISQELEE 95.00% 85.6 38.2 75 93 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 AQKSQSTQISQELEEL 95.00% 85 40.6 79 94 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 AQKSQSTQISQELEE 95.00% 84.1 40.5 79 93 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 MAQKSQSTQISQELEELR 95.00% 81.7 41.6 78 95 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 AQKSQSTQISQELE 95.00% 74.9 40.6 79 92 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 GDQMAQKSQSTQISQELEELR 95.00% 71.2 40.7 75 95 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491GDQMAQKSQSTQISQELEELRAEQQ 95.00% 65.6 41.9 73 101 FCER2 Isoform A of Low affinity immunoglobulin epsilon Fc receptor IPI00027491 DQMAQKSQSTQISQELEELR 93.80% 53.8 40.7 76 95 FLOT1 Flotillin-1 IPI00027438 SQLIMQAEAEAASVR 95.00% 109 39.5 62 76 FLT1 Isoform Flt1 of Vascular endothelial growth factor receptor 1 IPI00018335 DADSNMGNRIESITQ 95.00% 59.6 37.4 493 507 FLT1 Isoform Flt1 of Vascular endothelial growth factor receptor 1 IPI00018335 IDQSNSHANIFYSVLT 93.70% 48.3 40.3 282 297 FLVCR1 Feline leukemia virus subgroup C receptor-related protein 1 IPI00022344 RPDDEEGAAVAPGHP 95.00% 98.9 38.9 3 17 FLVCR1 Feline leukemia virus subgroup C receptor-related protein 1 IPI00022344 DDEEGAAVAPGHP 95.00% 84.8 34.7 5 17 FLVCR1 Feline leukemia virus subgroup C receptor-related protein 1 IPI00022344 TPLAPEEETQARLLPAGAG 95.00% 83.6 40.9 69 87 FLVCR1 Feline leukemia virus subgroup C receptor-related protein 1 IPI00022344 TPLAPEEETQARLLPAG 95.00% 66.9 40.3 69 85 FLVCR1 Feline leukemia virus subgroup C receptor-related protein 1 IPI00022344 APEEETQARLLPAGAG 95.00% 65.2 39.9 72 87 FTL Ferritin light polypeptide variant IPI00375676 IRQNYSTDVEAAVN 95.00% 92.8 40.7 5 18 FTL Ferritin light polypeptide variant IPI00375676 IRQNYSTDVEAAVNSL 95.00% 88.6 40.6 5 20 FTL Ferritin light polypeptide variant IPI00375676 IRQNYSTDVEAAVNS 95.00% 80.4 40.3 5 19 Diabetes Page 32 of 49

FTMT Ferritin, mitochondrial IPI00166689 DSEAAINRQINLE 95.00% 76.1 39.9 75 87 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205QPDGTPGGSGAAVAPAAGQGSHS 95.00% 118 38.3 35 57 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 TPGGSGAAVAPAAGQGSHS 95.00% 117 39 39 57 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 TPGGSGAAVAPAAGQGSHSRQ 95.00% 116 40.4 39 59 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 TPGGSGAAVAPAAGQGSH 95.00% 110 39.3 39 56 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 TPGGSGAAVAPAAGQG 95.00% 89.7 38.7 39 54 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 QPDGTPGGSGAAVAPAAGQG 95.00% 64.8 39.9 35 54 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 GTPGGSGAAVAPAAGQGSHS 95.00% 61.7 38.9 38 57 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 TPGGSGAAVAPAAGQ 95.00% 55.2 38.3 39 53 GALNT10 Isoform 1 of Polypeptide N-acetylgalactosaminyltransferase 10 IPI00375205 GTPGGSGAAVAPAAGQGSHSRQ 94.10% 54.3 40.4 38 59 GALNT2 Polypeptide N-acetylgalactosaminyltransferase 2 IPI00004669 EAYVGGTMVRSGQDPY 95.00% 110 36.7 84 99 GALNT2 Polypeptide N-acetylgalactosaminyltransferase 2 IPI00004669 EAYVGGTMVRSGQDPYA 95.00% 94.6 37.8 84 100 GALNT2 Polypeptide N-acetylgalactosaminyltransferase 2 IPI00004669 AYVGGTMVRSGQDPY 95.00% 83.4 38.9 85 99 GALNT2 Polypeptide N-acetylgalactosaminyltransferase 2 IPI00004669 EAYVGGTMVRSGQDP 95.00% 79.9 37.7 84 98 GAPDH Glyceraldehyde-3-phosphate dehydrogenase IPI00219018 FRVPTANVS 95.00% 61.7 39.8 233 241 GAPDH Glyceraldehyde-3-phosphate dehydrogenase IPI00219018 EGLMTTVHAITATQ 95.00% 59.8 41 172 185 GAPDH Glyceraldehyde-3-phosphate dehydrogenase IPI00219018 MAHMASKE 95.00% 49.6 38.5 328 335 GART Isoform Long of Trifunctional purine biosynthetic protein adenosine-3 IPI00025273 EAWVIGSVVARAEG 95.00% 77 38.8 759 772 GART Isoform Long of Trifunctional purine biosynthetic protein adenosine-3 IPI00025273DIQQHKEEAWVIGSVVARAEGSPR 95.00% 76.9 41.9 752 775 GART Isoform Long of Trifunctional purine biosynthetic protein adenosine-3 IPI00025273 EEAWVIGSVVARAEGSPR 95.00% 73.1 41.5 758 775 GART Isoform Long of Trifunctional purine biosynthetic protein adenosine-3 IPI00025273 EAWVIGSVVARAEGSPR 95.00% 60.5 39.8 759 775 GLG1 golgi apparatus protein 1 IPI00414717 IEMWSYAAKVAPAD 95.00% 93.7 40.6 1116 1129 GLG1 golgi apparatus protein 1 IPI00414717 IEMWSYAAKVAPADG 95.00% 88.1 39.8 1116 1130 GLG1 golgi apparatus protein 1 IPI00414717 GEKGNLGMNCQQALQ 95.00% 72.1 38.6 471 485 GOLIM4 Golgi integral membrane protein 4 IPI00004962 MALQRQAELEEGRPQHQ 88.00% 45.2 40.9 458 474 GOT1 Aspartate aminotransferase, cytoplasmic IPI00219029 NLDYVATSIHEAVTK 95.00% 104 40.9 397 411 GOT1 Aspartate aminotransferase, cytoplasmic IPI00219029 NLDYVATSIHEAVT 95.00% 87.1 40.1 397 410 HGFAC Hepatocyte growth factor activator IPI00029193 SPEVYGADISPNM 95.00% 80.6 37 569 581 HLA-DMB HLA class II histocompatibility antigen, DM beta chain IPI00000793 GVLNSLANVLSQH 95.00% 67.2 38.8 67 79 HLA-DMB HLA class II histocompatibility antigen, DM beta chain IPI00000793 GVLNSLANVLSQHLN 95.00% 65 39.5 67 81 HLA-DPA1 HLA class II histocompatibility antigen, DP alpha chain IPI00021711 IKADHVSTYAAFVQTHRPT 95.00% 82.2 41.4 32 50 HLA-DPA1 HLA class II histocompatibility antigen, DP alpha chain IPI00021711 IKADHVSTYAAFVQTHRPTG 95.00% 65.9 41.4 32 51 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 SFEAQGALANIAVDK 95.00% 145 40.4 94 108 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 ASFEAQGALANIAVDK 95.00% 131 40.1 93 108 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 SFEAQGALANIAVDKAN 95.00% 127 40.9 94 110 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 ASFEAQGALANIAVDKA 95.00% 125 40.8 93 109 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 ASFEAQGALANIAVDKAN 95.00% 124 40.6 93 110 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 FEAQGALANIAVDK 95.00% 123 41.6 95 108 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 SFEAQGALANIAVDKA 95.00% 119 40.7 94 109 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 FEAQGALANIAVDKAN 95.00% 117 40.8 95 110 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 FEAQGALANIAVDKA 95.00% 104 39.9 95 109 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 ASFEAQGALANIAVD 95.00% 95 40.2 93 107 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 EAQGALANIAVDKA 95.00% 93.2 40.2 96 109 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 EAQGALANIAVDK 95.00% 92.7 40.3 96 108 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 EAQGALANIAVDKAN 95.00% 90.5 39.7 96 110 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 SFEAQGALANIAVD 95.00% 83.9 40.2 94 107 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 TVLTNSPVELREPNV 95.00% 86.6 38.5 131 145 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 TVLTNSPVELREPNVL 95.00% 71.9 38.3 131 146 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 VLTNSPVELREPNV 95.00% 68.7 39.1 132 145 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 VLTNSPVELREPNVL 95.00% 66.6 38.2 132 146 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 TNSPVELREPNVL 95.00% 60.8 39.5 134 146 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 TVLTNSPVELREPNVLI 95.00% 60 37.1 131 147 HLA-DRA HLA class II histocompatibility antigen, DR alpha chain IPI00005171 VLTNSPVELREPNVLI 95.00% 53.5 36.6 132 147 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSND 95.00% 141 38.9 154 170 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSND 95.00% 139 39.6 155 170 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSN 95.00% 136 39.9 154 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQK 95.00% 126 39.5 154 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 SWTAVDTAAQISEQK 95.00% 125 40.1 153 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQK 95.00% 125 39.5 155 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSN 95.00% 116 40.4 155 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDASEAE 95.00% 116 37.9 155 175 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 AVDTAAQISEQKSND 95.00% 115 39.8 156 170 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 AVDTAAQISEQK 95.00% 113 40 156 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 AVDTAAQISEQKSNDA 95.00% 113 39.9 156 171 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSNDAS 95.00% 112 38.8 154 172 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDASEA 95.00% 111 39.3 155 174 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSNDA 95.00% 110 39.2 154 171 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 AVDTAAQISEQKSN 95.00% 109 40.4 156 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKS 95.00% 109 40.9 155 168 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDA 95.00% 105 39.7 155 171 Page 33 of 49 Diabetes

HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDASEAEHQ 95.00% 105 38.2 155 177 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSNDASEAE 95.00% 101 37.9 154 177 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 SWTAVDTAAQISEQKSN 95.00% 100 39.8 153 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDASEAE 95.00% 99.8 38.1 155 176 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKS 95.00% 94.2 40.1 154 168 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 DTAAQISEQKSN 95.00% 97.3 40 158 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDASEAEH 95.00% 93.7 39.4 155 178 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 VDTAAQISEQK 95.00% 93.3 41.6 157 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 DTAAQISEQKSNDA 95.00% 90.3 38.6 158 171 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQ 95.00% 90.3 39.2 154 166 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDAS 95.00% 89.2 39.4 155 172 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 AVDTAAQISEQKSNDASEAEH 95.00% 84.9 39.8 156 178 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 DTAAQISEQK 95.00% 80.7 40.3 158 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAAQISEQKSN 95.00% 79.3 40.4 159 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 AVDTAAQISEQKS 95.00% 78.4 41 156 168 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 AVDTAAQISEQKSNDASEAE 95.00% 77.2 38.2 156 177 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 VDTAAQISEQKSND 95.00% 73.3 39.7 157 170 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 DTAAQISEQKSND 95.00% 71.8 38.8 158 170 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAAQISEQKSND 95.00% 70.1 37.7 159 170 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSNDASEAEH 95.00% 70 39.2 154 178 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 DTAAQISEQKSNDASEAE 95.00% 67.8 35.7 158 177 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 VDTAAQISEQKSN 95.00% 65.2 40.4 157 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSNDASEAE 95.00% 64.7 37.7 154 176 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAAQISEQKSNDA 95.00% 64 37.3 159 171 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 DLRSWTAVDTAAQISEQK 95.00% 63.3 41.3 150 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 EDLRSWTAVDTAAQISEQKSN 95.00% 63 41.1 149 169 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAAQISEQK 95.00% 56.6 41.4 159 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQKSNDASEAEH 95.00% 51.7 39.7 155 179 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TAVDTAAQISEQ 95.00% 51.5 39.4 155 166 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 WTAVDTAAQISEQKSNDASEAEH 95.00% 51.3 39.4 154 179 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 EDLRSWTAVDTAAQISEQK 92.20% 51.2 41.2 149 167 HLA-E major histocompatibility complex, class I, E precursor IPI00010362 TQDTELVETRPAGDG 95.00% 69.2 39.4 246 260 HLA-F major histocompatibility complex, class I, F isoform 1 precursor IPI00294547 EWTTGYAKANAQTDR 95.00% 73.2 39.3 82 96 HLA-F major histocompatibility complex, class I, F isoform 1 precursor IPI00294547 TQDTELVETRPAGDG 95.00% 69.2 39.4 246 260 HLA-G HLA class I histocompatibility antigen, alpha chain G IPI00015988 LALNEDLRSWTAADTAAQ 95.00% 106 41.1 148 165 HLA-G HLA class I histocompatibility antigen, alpha chain G IPI00015988 LALNEDLRSWTAADT 95.00% 86.6 40.4 148 162 HLA-G HLA class I histocompatibility antigen, alpha chain G IPI00015988 LALNEDLRSWTAADTA 95.00% 74.8 40.2 148 163 HLA-G HLA class I histocompatibility antigen, alpha chain G IPI00015988 LALNEDLRSWTAAD 95.00% 61.9 39.3 148 161 HLA-G HLA class I histocompatibility antigen, alpha chain G IPI00015988 LALNEDLRSWTAADTAA 95.00% 59.6 40.3 148 164 HSP90AA2 Putative heat shock protein HSP 90-alpha A2 IPI00031523 DLINNLGTIAKSGTK 95.00% 84.7 38.5 102 116 HSP90AA2 Putative heat shock protein HSP 90-alpha A2 IPI00031523 DLINNLGTIAKSGTKA 95.00% 80.5 38.1 102 117 HSP90B1 Endoplasmin IPI00027230 DSNEFSVIADPRG 95.00% 78.3 37.7 226 238 HSP90B1 Endoplasmin IPI00027230 ESDSNEFSVIADPRGN 95.00% 69.2 37 224 239 HSP90B1 Endoplasmin IPI00027230 ESDSNEFSVIADPRGNT 95.00% 67.7 36.9 224 240 HSP90B1 Endoplasmin IPI00027230 SDSNEFSVIADPRG 95.00% 65.8 38.5 225 238 HSPA13 Stress 70 protein chaperone microsome-associated 60 kDa protein IPI00299299 AVVTGVAIQAGIDGG 95.00% 111 39.1 435 449 HSPA13 Stress 70 protein chaperone microsome-associated 60 kDa protein IPI00299299 VINEPTAAAMAYGLH 95.00% 107 38.7 200 214 HSPA13 Stress 70 protein chaperone microsome-associated 60 kDa protein IPI00299299 RVINEPTAAAMAYGLH 95.00% 73.6 40.1 199 214 HSPA13 Stress 70 protein chaperone microsome-associated 60 kDa protein IPI00299299 LRVINEPTAAAMAYGLH 95.00% 64.4 40.8 198 214 HSPA13 Stress 70 protein chaperone microsome-associated 60 kDa protein IPI00299299 RVINEPTAAAMAYG 95.00% 62.9 39.8 199 212 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 INEPTAAAIAYGLDRTG 95.00% 123 41.1 173 189 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 INEPTAAAIAYGLDRT 95.00% 113 40.2 173 188 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 INEPTAAAIAYGLDR 95.00% 110 39.8 173 187 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 IINEPTAAAIAYGLDRTG 95.00% 108 40.4 172 189 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 IINEPTAAAIAYGLD 95.00% 96.2 40.1 172 186 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 IINEPTAAAIAYGL 95.00% 90.5 39.5 172 185 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 LRIINEPTAAAIAYGLD 95.00% 81 39.7 170 186 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 RIINEPTAAAIAYGL 95.00% 72 39.6 171 185 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 ALESYAFNMKSAVEDEG 95.00% 68.4 37.1 541 557 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 RIINEPTAAAIAYGLD 95.00% 64.8 40.5 171 186 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 LRIINEPTAAAIAYG 95.00% 61.3 39.3 170 184 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 RIINEPTAAAIAYG 95.00% 61.2 38.8 171 184 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 EPTAAAIAYGLD 95.00% 52.9 40.9 175 186 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 INEPTAAAIAYGLDRTGKGE 91.70% 50.4 41.3 173 192 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 INEPTAAAIAYGL 86.80% 45 40.2 173 185 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 AKRTLSSSTQASLEIDS 90.80% 49 41.3 270 286 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 AKRTLSSSTQASLEID 89.60% 46.3 40.1 270 285 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 GAAVQAAILMGDKSEN 95.00% 94.7 41 372 387 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 EAVAYGAAVQAA 90.30% 46 39.9 367 378 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 NPDEAVAYGAAVQAA 95.00% 57.8 39 364 378 Diabetes Page 34 of 49

HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 NPDEAVAYGAAVQAAI 95.00% 51.3 40.5 364 379 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 SDNQPGVLIQVYEGER 95.00% 105 40.3 432 447 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 NALESYAFNMKSAVEDEG 95.00% 98.7 36.6 540 557 HSPA1B;HSPA1A Heat shock 70 kDa protein 1 IPI00304925 DLNKSINPDEAVA 95.00% 52.8 40.7 358 370 HSPA5 HSPA5 protein IPI00003362 TASDNQPTVTIKVYEGERP 93.80% 54.5 41.4 454 472 HSPA5 HSPA5 protein IPI00003362 EAVAYGAAVQAGVLS 95.00% 78.1 40.4 393 407 HSPA5 HSPA5 protein IPI00003362 IINEPTAAAIAYGLDK 95.00% 128 40.6 199 214 HSPA5 HSPA5 protein IPI00003362 INEPTAAAIAYGLDK 95.00% 112 40.5 200 214 HSPA5 HSPA5 protein IPI00003362 NEPTAAAIAYGLDK 95.00% 104 39.9 201 214 HSPA5 HSPA5 protein IPI00003362 IINEPTAAAIAYGLD 95.00% 96.2 40.1 199 213 HSPA5 HSPA5 protein IPI00003362 IINEPTAAAIAYGL 95.00% 90.5 39.5 199 212 HSPA5 HSPA5 protein IPI00003362 EPTAAAIAYGLDK 95.00% 77.1 40.7 202 214 HSPA5 HSPA5 protein IPI00003362 RIINEPTAAAIAYGL 95.00% 72 39.6 198 212 HSPA5 HSPA5 protein IPI00003362 RIINEPTAAAIAYGLD 95.00% 64.8 40.5 198 213 HSPA5 HSPA5 protein IPI00003362 RIINEPTAAAIAYG 95.00% 61.2 38.8 198 211 HSPA5 HSPA5 protein IPI00003362 EPTAAAIAYGLD 95.00% 52.9 40.9 202 213 HSPA5 HSPA5 protein IPI00003362 IINEPTAAAIAYGLDKREGEKN 95.00% 45.5 41.3 199 220 HSPA5 HSPA5 protein IPI00003362 INEPTAAAIAYGL 86.80% 45 40.2 200 212 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 IINEPTAAAIAYGLDK 95.00% 128 40.6 172 187 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 INEPTAAAIAYGLDK 95.00% 112 40.5 173 187 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 IINEPTAAAIAYGLDKK 95.00% 110 39.1 172 188 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 INEPTAAAIAYGLDKK 95.00% 107 39.5 173 188 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 NEPTAAAIAYGLDK 95.00% 104 39.9 174 187 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 IINEPTAAAIAYGLD 95.00% 96.2 40.1 172 186 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 IINEPTAAAIAYGL 95.00% 90.5 39.5 172 185 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 RIINEPTAAAIAYGLDKK 95.00% 88.8 37.8 171 188 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 INEPTAAAIAYGLDKKVG 95.00% 88.5 39.7 173 190 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 NEPTAAAIAYGLDKK 95.00% 85.1 39.9 174 188 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 INEPTAAAIAYGLDKKV 95.00% 82.8 38.9 173 189 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 LRIINEPTAAAIAYGLD 95.00% 81 39.7 170 186 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 EPTAAAIAYGLDK 95.00% 77.1 40.7 175 187 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 EPTAAAIAYGLDKK 95.00% 74.3 40.5 175 188 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 RIINEPTAAAIAYGL 95.00% 72 39.6 171 185 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 EPTAAAIAYGLDKKVG 95.00% 69.1 39.7 175 190 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 RIINEPTAAAIAYGLD 95.00% 64.8 40.5 171 186 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 INEPTAAAIAYGL 86.80% 45 40.2 173 185 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 LRIINEPTAAAIAYG 95.00% 61.3 39.3 170 184 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 RIINEPTAAAIAYG 95.00% 61.2 38.8 171 184 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 EPTAAAIAYGLD 95.00% 52.9 40.9 175 186 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 GKELNKSINPDEAVAYG 95.00% 60.7 41.2 356 372 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 KELNKSINPDEAVAYG 95.00% 59.1 40.8 357 372 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 ELNKSINPDEAVA 95.00% 52.5 40.7 358 370 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 GKELNKSINPDEAVA 95.00% 50.8 40.4 356 370 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 KELNKSINPDEAVA 95.00% 64.7 40.3 357 370 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 ELNKSINPDEAVAYG 95.00% 72.2 40.5 358 372 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 AKRTLSSSTQASIEIDS 90.80% 49 41.3 270 286 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 AKRTLSSSTQASIEID 89.60% 46.3 40.1 270 285 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 NPDEAVAYGAAVQAAILSGDKS 95.00% 125 41.7 364 385 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 NPDEAVAYGAAVQAA 95.00% 57.8 39 364 378 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 EAVAYGAAVQAAILSG 95.00% 86 40.2 367 382 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 NPDEAVAYGAAVQAAI 95.00% 51.3 40.5 364 379 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 EAVAYGAAVQAA 90.30% 46 39.9 367 378 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 DKSQIHDIVLVGGSTR 89.50% 45.5 39.5 327 342 HSPA8 Isoform 1 of Heat shock cognate 71 kDa protein IPI00003865 SDNQPGVLIQVYEGER 95.00% 105 40.3 432 447 HSPB1 Heat shock protein beta-1 IPI00025512 TVEAPMPKLATQSNE 95.00% 66.9 40.9 34 48 ICAM1 Intercellular adhesion molecule 1 IPI00008494 LFPVSEAQVHLALGDQ 95.00% 105 40.1 242 257 ICAM3 Intercellular adhesion molecule 3 IPI00031620 EPAEVTATVLASRDD 95.00% 90.1 41.1 169 183 ICAM3 Intercellular adhesion molecule 3 IPI00031620 GDTLTATATATARADQ 95.00% 125 39.8 271 286 ICAM3 Intercellular adhesion molecule 3 IPI00031620 GDTLTATATATARADQ E 95.00% 103 40 271 287 ICAM3 Intercellular adhesion molecule 3 IPI00031620 HGDTLTATATATARADQ 95.00% 84.4 39.4 270 286 ICAM3 Intercellular adhesion molecule 3 IPI00031620 HGDTLTATATATARADQEG 95.00% 68.8 39.7 270 288 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 MVGDVTGAQAYASTAK 95.00% 135 39.2 89 104 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 VGDVTGAQAYASTAK 95.00% 117 39 90 104 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 GDVTGAQAYASTAK 95.00% 104 39.9 91 104 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 VGDVTGAQAYAST 95.00% 90.5 39.6 90 102 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 DRKMVGDVTGAQAYASTAK 95.00% 87.8 40.5 86 104 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 DVTGAQAYASTA 95.00% 74.4 38.1 92 103 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 DVTGAQAYASTAK 95.00% 70.3 39.3 92 104 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 VTGAQAYASTAK 95.00% 62.5 39.9 93 104 IFITM2 Interferon-induced transmembrane protein 2 IPI00008922 DVTGAQAYAS 95.00% 45.1 38.3 92 101 Page 35 of 49 Diabetes

IFNGR1 Interferon-gamma receptor alpha chain IPI00010808 VLHVWGVTTEKSKE 94.40% 53.2 38.6 186 199 IFNGR1 Interferon-gamma receptor alpha chain IPI00010808 GVLHVWGVTTEKSKE 91.10% 47.1 38.8 185 199 Ig kappa chain V-III region NG9 (Fragment) IPI00387116 KPGQAPRLLIYGATSRATG 94.50% 52.8 37.9 44 62 Ig kappa chain V-III region NG9 (Fragment) IPI00387116 KPGQAPRLLIYGATSRATGIP 94.30% 51 36.7 44 64 Ig lambda chain V-II region BUR IPI00003947 KSGNTASLTISGLQ 95.00% 87.7 39.3 87 100 IGF2R Cation-independent mannose-6-phosphate receptor IPI00289819 TDTDQACSIRDPNSG 95.00% 80 33.8 928 942 IGF2R Cation-independent mannose-6-phosphate receptor IPI00289819 KPASGCEAETQTEEL 95.00% 47.7 37.7 982 996 IGHG1 Putative uncharacterized protein DKFZp686H20196 IPI00423466 NWYVDGVEVHNAK 95.00% 87.5 39.7 309 321 IGHG1 Putative uncharacterized protein DKFZp686H20196 IPI00423466 GALTSGVHTFPAVLQ 95.00% 69.6 38.4 194 208 IGHG1 Putative uncharacterized protein DKFZp686H20196 IPI00423466 GALTSGVHTFPAVL 95.00% 57.3 37.8 194 207 IGHG1 Putative uncharacterized protein DKFZp686H20196 IPI00423466 GALTSGVHTFPAVLQS 93.40% 48.6 40.9 194 209 IGHG1 Putative uncharacterized protein DKFZp686P15220 IPI00645363 NWYVDGVEVHNAK 95.00% 87.5 39.7 301 313 IGHG1 Putative uncharacterized protein DKFZp686P15220 IPI00645363 LVESGGGLVQPGRSL 95.00% 68.7 38.4 23 37 IGHG1 Putative uncharacterized protein DKFZp686P15220 IPI00645363 LVESGGGLVQPGRS 95.00% 84.9 39.3 23 36 IGHG1 Putative uncharacterized protein DKFZp686P15220 IPI00645363 GALTSGVHTFPAVLQ 95.00% 69.6 38.4 186 200 IGHG1 Putative uncharacterized protein DKFZp686P15220 IPI00645363 GALTSGVHTFPAVL 95.00% 57.3 37.8 186 199 IGHG1 Putative uncharacterized protein DKFZp686P15220 IPI00645363 GALTSGVHTFPAVLQS 93.40% 48.6 40.9 186 201 IGHM IGHM protein IPI00477090 LVESGGGVVQPGRS 95.00% 86.6 38.3 23 36 IGHM IGHM protein IPI00477090 LVESGGGVVQPGRSL 95.00% 85.1 39.3 23 37 IGHM IGHM protein IPI00477090 ESGGGVVQPGRS 95.00% 78.5 38.8 25 36 IGHM IGHM protein IPI00477090 TGETYTCVVAHEALPNR 95.00% 97.8 40.2 546 562 IGHM IGHM protein IPI00477090 GETYTCVVAHEALPN 95.00% 63.5 39.1 547 561 IGHM IGHM protein IPI00477090 TGETYTCVVAHEALP 95.00% 50.8 39.4 546 560 IGHM IGHM protein IPI00477090 SPRQIQVSWLREGKQ 91.50% 48.2 39.3 279 293 IGHM IGHM protein IPI00477090 TDQVQAEAKESGPT 95.00% 69.9 40.1 300 313 IGHM IGHM protein IPI00477090 SDISSTRGFPSVL 85.80% 45.2 40.6 187 199 IGHV4-31 Anti-RhD monoclonal T125 gamma1 heavy chain IPI00784817 NWYVDGVEVHNAK 95.00% 87.5 39.7 304 316 IGHV4-31 Anti-RhD monoclonal T125 gamma1 heavy chain IPI00784817 LVESGGGVVQPGRS 95.00% 86.6 38.3 23 36 IGHV4-31 Anti-RhD monoclonal T125 gamma1 heavy chain IPI00784817 LVESGGGVVQPGRSL 95.00% 85.1 39.3 23 37 IGHV4-31 Anti-RhD monoclonal T125 gamma1 heavy chain IPI00784817 ESGGGVVQPGRS 95.00% 78.5 38.8 25 36 IGHV4-31 Anti-RhD monoclonal T125 gamma1 heavy chain IPI00784817 GALTSGVHTFPAVLQ 95.00% 69.6 38.4 189 203 IGHV4-31 Anti-RhD monoclonal T125 gamma1 heavy chain IPI00784817 GALTSGVHTFPAVL 95.00% 57.3 37.8 189 202 IGHV4-31 Anti-RhD monoclonal T125 gamma1 heavy chain IPI00784817 GALTSGVHTFPAVLQS 93.40% 48.6 40.9 189 204 IGKV1-5 IGKV1-5 protein IPI00419424 GNSQESVTEQDSKDST 95.00% 105 34.8 179 194 IGKV1-5 IGKV1-5 protein IPI00419424 SGNSQESVTEQDSKDS 95.00% 101 33.3 178 193 IGKV1-5 IGKV1-5 protein IPI00419424 NSQESVTEQDSKDST 95.00% 92.3 34.7 180 194 IGKV1-5 IGKV1-5 protein IPI00419424 NSQESVTEQDSKD 95.00% 87.7 35.6 180 192 IGKV1-5 IGKV1-5 protein IPI00419424 NSQESVTEQDSKDS 95.00% 83.2 35.3 180 193 IGKV1-5 IGKV1-5 protein IPI00419424 SGNSQESVTEQDSKDST 95.00% 81.6 34.2 178 194 IGKV1-5 IGKV1-5 protein IPI00419424 GNSQESVTEQDSKDS 95.00% 81 34.4 179 193 IGKV3D-15 Myosin-reactive immunoglobulin light chain variable region IPI00549330 KPGQAPRLLIYGASTRATGIPA 95.00% 82.1 36.4 59 80 IGKV3D-15 Myosin-reactive immunoglobulin light chain variable region IPI00549330 LLIYGASTRATG 95.00% 63.1 39 66 77 IGKV3D-15 Myosin-reactive immunoglobulin light chain variable region IPI00549330 APRLLIYGASTRATG 95.00% 55.6 38.5 63 77 IGKV3D-15 Myosin-reactive immunoglobulin light chain variable region IPI00549330 LLIYGASTRATGIP 95.00% 55 38.1 66 79 IGSF8 Isoform 1 of Immunoglobulin superfamily member 8 IPI00056478 APYAERLAAGELRLGKEGTD 90.60% 48.4 40.8 101 120 IL21R Interleukin-21 receptor IPI00034249 ELQEPAELVESDG 95.00% 68.9 37.4 355 367 IL4R Isoform 1 of Interleukin-4 receptor alpha chain IPI00444383 NVLQHGAAAAPVSAPT 95.00% 52.4 39.5 557 572 IL6ST Isoform 1 of Interleukin-6 receptor subunit beta IPI00297124 SSQNTSSTVQYSTVVH 95.00% 135 39 688 703 IL6ST Isoform 1 of Interleukin-6 receptor subunit beta IPI00297124 ESSQNTSSTVQYSTVVH 95.00% 71.5 39 687 703 IL6ST Isoform 1 of Interleukin-6 receptor subunit beta IPI00297124 SSQNTSSTVQYSTVV 95.00% 68 39.8 688 702 IL6ST Isoform 1 of Interleukin-6 receptor subunit beta IPI00297124 VGKNEAVLEWDQLPVD 95.00% 68.6 40.8 469 484 IL6ST Isoform 1 of Interleukin-6 receptor subunit beta IPI00297124 KNEAVLEWDQLPVD 95.00% 61.3 39.7 471 484 IRGQ Immunity-related GTPase family Q protein IPI00103925 RPGDSQTAAQARDQTA 95.00% 76 39.5 117 132 IRGQ Immunity-related GTPase family Q protein IPI00103925 RPGDSQTAAQARDQTAA 95.00% 66.9 40 117 133 IRGQ Immunity-related GTPase family Q protein IPI00103925 RPGDSQTAAQARDQ 95.00% 59.7 38.3 117 130 ITCH Isoform 1 of E3 ubiquitin-protein ligase Itchy homolog IPI00061780 LPPTNTNTNTSEGATSG 95.00% 79.6 38.6 288 304 ITFG3 Isoform 2 of Protein ITFG3 IPI00396658 VPGNAGADVLLVGSE 95.00% 49.7 40.5 334 348 ITGA4 Integrin alpha-4 IPI00009803 SDVITGSIQVSSREAN 95.00% 84.7 40.9 546 561 ITGA4 Integrin alpha-4 IPI00009803 SDVITGSIQVSSRE 95.00% 76.4 40.4 546 559 ITGA4 Integrin alpha-4 IPI00009803 EDDLQGAIYIYNGRADG 95.00% 71.2 38.4 398 414 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 YEDSLSSQVRTQME 95.00% 111 37.6 53 66 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 YEDSLSSQVRTQMELE 95.00% 108 38.4 53 68 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 EDSLSSQVRTQMELE 95.00% 92.7 38.3 54 68 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 LYEDSLSSQVRTQME 95.00% 81.6 39.1 52 66 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 EDSLSSQVRTQME 95.00% 76.5 37.9 54 66 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 DSLSSQVRTQMELE 95.00% 76.2 39.1 55 68 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 EDSLSSQVRTQMELEE 95.00% 71.9 38.3 54 69 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 DSLSSQVRTQME 95.00% 69.7 38.6 55 66 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 YEDSLSSQVRTQMEL 95.00% 61.2 38.4 53 67 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 EDSLSSQVRTQ 95.00% 61 39.5 54 64 Diabetes Page 36 of 49

ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 EDSLSSQVRTQMEL 95.00% 55.1 40.1 54 67 ITM2C Isoform 1 of Integral membrane protein 2C IPI00016014 GDKADKASASAPAPASATE 94.20% 53.8 39.7 15 33 KCNN3 Small-conductance calcium-activated potassium channel SK3 IPI00032465 APPSSNSTAILHPSSRQ 95.00% 67.7 40.5 116 132 KCNN3 Small-conductance calcium-activated potassium channel SK3 IPI00032465 APPSSNSTAILHPSSR 95.00% 66.8 39.9 116 131 KCNN3 Small-conductance calcium-activated potassium channel SK3 IPI00032465 APPSSNSTAILHPSSRQG 95.00% 64.8 40.5 116 133 KIAA0174 Isoform 1 of Uncharacterized protein KIAA0174 IPI00024660 LPTASAGASTSASEDID 95.00% 93.1 38.7 304 320 KIAA0174 Isoform 1 of Uncharacterized protein KIAA0174 IPI00024660 ADKNISSAQIVGPGP 95.00% 60.1 40.2 259 273 KIAA0494 Uncharacterized calcium-binding protein KIAA0494 IPI00006130 LEEVNSALVGYQRQND 95.00% 99.5 40.4 274 289 KIAA0494 Uncharacterized calcium-binding protein KIAA0494 IPI00006130 SLEEVNSALVGYQRQNDL 95.00% 83.7 41.4 273 290 KIAA0494 Uncharacterized calcium-binding protein KIAA0494 IPI00006130 ASIGNTLNSVHLAVE 95.00% 57.8 40.1 196 210 KIAA0494 Uncharacterized calcium-binding protein KIAA0494 IPI00006130 ASIGNTLNSVHLAVEALQ 91.10% 46.2 39.7 196 213 KIAA1109 Isoform 1 of Uncharacterized protein KIAA1109 IPI00852643 DGIAIGAALLPSLK 95.00% 72.1 33.9 2984 2997 KIAA1109 Isoform 1 of Uncharacterized protein KIAA1109 IPI00852643 SKGGVVGGTIDVN 95.00% 52.5 41.7 4461 4473 KIAA1618 Isoform 1 of Protein ALO17 IPI00642126 TEQQAGASASMAVDAV 95.00% 57.8 38.1 260 275 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 DLDNWTALISASKE 95.00% 114 40.3 68 81 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 EDLDNWTALISASKE 95.00% 95.8 40.2 67 81 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 LDNWTALISASKE 95.00% 95 41.4 69 81 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 DNWTALISASKEGH 95.00% 86 38.4 70 83 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 DNWTALISASKE 95.00% 75 39.9 70 81 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 EDLDNWTALISASKEGH 95.00% 71.8 40 67 83 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 DLDNWTALISASK 95.00% 60.9 40.6 68 80 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 LDNWTALISASKEGH 95.00% 59 39.1 69 83 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 EDLDNWTALISASKEGHVH 95.00% 57.4 40.2 67 85 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 EDLDNWTALISASK 95.00% 57.3 40.5 67 80 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 EGANSMTALIVAVK 95.00% 83.8 39.4 199 212 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 DPPELHAAASSESTGFG 95.00% 64.3 36.2 1748 1764 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 KSDQSGSKLLPGK 95.00% 60.2 39.1 1482 1494 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 EDEKSDQSGSKLLPGK 90.90% 48 40.1 1479 1494 KIDINS220 Isoform 2 of Ankyrin repeat-rich membrane spanning protein IPI00384909 EDEKSDQSGSKLLPGKK 89.90% 47.2 40.7 1479 1495 KRT10 Keratin, type I cytoskeletal 10 IPI00009865 SSGSVGESSSKGP 95.00% 75.1 37.3 547 559 KRT10 Keratin, type I cytoskeletal 10 IPI00009865 SVGESSSKGP 95.00% 63.4 40.4 550 559 KRT9 Keratin, type I cytoskeletal 9 IPI00019359 SRSGGGGGGGLGSGGSIRSSY 95.00% 76.9 39.7 12 32 KRT9 Keratin, type I cytoskeletal 9 IPI00019359 LSRSGGGGGGGLGSGGSIRSS 95.00% 69.1 40.6 11 31 LAMP3 Lysosome-associated membrane glycoprotein 3 IPI00004307 YQGIKHAVVMFQTAVG 95.00% 75.6 40.1 319 334 LAPTM5 Lysosomal-associated transmembrane protein 5 IPI00013827 IEHSVEVAHGKAS 93.60% 52.8 40.1 37 49 LASP1 Isoform 1 of LIM and SH3 domain protein 1 IPI00000861 DDGWMYGTVERTGDTG 95.00% 85.3 31.8 236 251 LASP1 Isoform 1 of LIM and SH3 domain protein 1 IPI00000861 IDDGWMYGTVERTGDTG 95.00% 65.6 35.1 235 251 LDHB L-lactate dehydrogenase B chain IPI00219217 ADELALVDVLEDK 95.00% 73 41.1 46 58 LDHB L-lactate dehydrogenase B chain IPI00219217 GVNVAGVSLQELNPE 95.00% 71.7 40.4 204 218 LDLR Low-density lipoprotein receptor IPI00000070 DTEVASNRIYWSDLS 95.00% 51 38.9 433 447 LFNG Isoform 1 of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe IPI00455739 APAPGLGAAAAAPGALVR 95.00% 95.2 36.6 52 69 LFNG Isoform 1 of Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe IPI00455739 APAPGLGAAAAAPGALV 95.00% 88.3 38.6 52 68 LGALS9 Isoform Long of Galectin-9 IPI00010477 ITVNGTVLSSSGTR 95.00% 115 38.4 31 44 LGALS9 Isoform Long of Galectin-9 IPI00010477 QITVNGTVLSSSGTR 95.00% 95 39.7 30 44 LGALS9 Isoform Long of Galectin-9 IPI00010477 SILLSGTVLPSAQR 95.00% 103 37.9 208 221 LGALS9 Isoform Long of Galectin-9 IPI00010477 SILLSGTVLPSAQRFH 95.00% 94.2 38 208 223 LGMN Legumain IPI00293303 VTPQNFLAVLRGDAEA 95.00% 90.8 40.4 108 123 LGMN Legumain IPI00293303 TPQNFLAVLRGDAE 95.00% 84.1 39.3 109 122 LGMN Legumain IPI00293303 VTPQNFLAVLRGDAE 95.00% 77.3 40.9 108 122 LGMN Legumain IPI00293303 TPQNFLAVLRGDAEA 95.00% 75.2 40.8 109 123 LGMN Legumain IPI00293303 VTPQNFLAVLRGDAEAV 95.00% 68.6 40.2 108 124 LGMN Legumain IPI00293303 DHGSTGILVFPNEDL 95.00% 79.1 40.2 147 161 LGMN Legumain IPI00293303 DHGSTGILVFPNED 95.00% 51.7 38.2 147 160 LGMN Legumain IPI00293303 TDHGSTGILVFPNED 95.00% 46.3 37.3 146 160 LILRB1 Uncharacterized protein LILRB1 IPI00020967 FLQLAGAQPQAGLSQ 95.00% 109 38.7 265 279 LIPA Isoform 1 of Lysosomal acid lipase/cholesteryl ester hydrolase IPI00007207 DMLVPTAVWSGGHD 95.00% 85.1 36.8 334 347 LMAN2 Vesicular integral-membrane protein VIP36 IPI00009950 TPDEESIDWTKIEPSVN 95.00% 98.9 39.3 281 297 LMAN2 Vesicular integral-membrane protein VIP36 IPI00009950 EESIDWTKIEPSVN 95.00% 63.9 39.7 284 297 LNPEP Isoform 2 of Leucyl-cystinyl aminopeptidase IPI00221240 AKLLGMSFMNRSSG 95.00% 61.2 37.9 74 87 LNPEP Isoform 2 of Leucyl-cystinyl aminopeptidase IPI00221240 SFMNRSSGLRNSATG 90.80% 47.1 39.3 80 94 LOC100133661;HLA-DRB4 IPI00107714 AQSESAQSKMLSGVGGFV 95.00% 104 40.3 219 236 LOC100133661;HLA-DRB4 IPI00107714 SESAQSKMLSGVGGFV 95.00% 101 40.7 221 236 LOC100133661;HLA-DRB4 IPI00107714 QSESAQSKMLSGVGGFV 95.00% 93 40.4 220 236 LOC100133661;HLA-DRB4 IPI00107714 QSESAQSKMLSGVGGF 95.00% 92.5 39.6 220 235 LOC100133661;HLA-DRB4 IPI00107714 SESAQSKMLSGVGGF 95.00% 86.9 40.1 221 235 LOC100133661;HLA-DRB4 IPI00107714 AQSESAQSKMLSGVGGF 95.00% 85.8 39.5 219 235 LOC100133661;HLA-DRB4 IPI00107714 QSESAQSKMLSGVGG 95.00% 77.2 37.8 220 234 LOC100133661;HLA-DRB4 IPI00107714 AQSESAQSKMLSGVGG 95.00% 71.8 39.4 219 234 LOC100133661;HLA-DRB4 IPI00107714 AQSESAQSKMLSGVGGFVL 95.00% 71.7 40.6 219 237 LOC100133661;HLA-DRB4 IPI00107714 WRAQSESAQSKMLSGVGGFV 92.10% 51.2 41.3 217 236 Page 37 of 49 Diabetes

LOC100133661;HLA-DRB4 IPI00107714 QSESAQSKMLSGVG 95.00% 48 38.9 220 233 LOC100133661;HLA-DRB4 IPI00107714 SGEVYTCQVEHPSVT 95.00% 70.8 36.8 196 210 LOC100133661;HLA-DRB4 IPI00107714 VPRSGEVYTCQVEHPS 95.00% 65.7 39.3 193 208 LOC100133661;HLA-DRB4 IPI00107714 VPRSGEVYTCQVEHPSVT 95.00% 56.5 40.4 193 210 LOC100133661;HLA-DRB4;LOC100133583;RNASE2;HLA-DRB5;HLA-DRB3;HLIPI00895783 SGEVYTCQVEHPSVT 95.00% 70.8 36.8 196 210 LOC100133661;HLA-DRB4;LOC100133583;RNASE2;HLA-DRB5;HLA-DRB3;HLIPI00895783 VPRSGEVYTCQVEHPS 95.00% 65.7 39.3 193 208 LOC100133661;HLA-DRB4;LOC100133583;RNASE2;HLA-DRB5;HLA-DRB3;HLIPI00895783 VPRSGEVYTCQVEHPSVT 95.00% 56.5 40.4 193 210 LOC100133661;HLA-DRB4;LOC100133583;RNASE2;HLA-DRB5;HLA-DRB3;HLIPI00895783 SESAQSKMLSGVGGFV 95.00% 101 40.7 221 236 LOC100133661;HLA-DRB4;LOC100133583;RNASE2;HLA-DRB5;HLA-DRB3;HLIPI00895783 SESAQSKMLSGVGGF 95.00% 86.9 40.1 221 235 LOC100133661;HLA-DRB4;LOC100133583;RNASE2;HLA-DRB5;HLA-DRB3;HLIPI00895783 RSESAQSKMLSGVG 94.80% 54.1 38.4 220 233 LOC100133661;HLA-DRB4;LOC100133583;RNASE2;HLA-DRB5;HLA-DRB3;HLIPI00895783 ARSESAQSKMLSGVGGF 94.20% 53.9 39.9 219 235 LOC284194 galectin-9 like IPI00472523 SIILSGTVLPSAQR 95.00% 103 37.9 241 254 LOC284194 galectin-9 like IPI00472523 SIILSGTVLPSAQRFH 95.00% 94.2 38 241 256 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 IALNEDLRSWTAADTAAQ 95.00% 106 41.1 148 165 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 DLRSWTAADTAAQITQ 95.00% 100 40.4 153 168 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 EDLRSWTAADTAAQITQ 95.00% 91.9 39.9 152 168 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 IALNEDLRSWTAADT 95.00% 86.6 40.4 148 162 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 DLRSWTAADTAAQIT 95.00% 76.7 40.6 153 167 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 IALNEDLRSWTAADTA 95.00% 74.8 40.2 148 163 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 EDLRSWTAADTAAQIT 95.00% 73 39.9 152 167 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 IALNEDLRSWTAAD 95.00% 61.9 39.3 148 161 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 EDLRSWTAADTAAQITQR 95.00% 60.7 40.5 152 169 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 IALNEDLRSWTAADTAA 95.00% 59.6 40.3 148 164 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 EDLRSWTAADTAAQITQRK 95.00% 58.7 40.9 152 170 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 DGEDQTQDTELVETRPAGDR 95.00% 79.6 37.4 244 263 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 DGEDQTQDTELVETRPAGDRT 95.00% 79 37.8 244 264 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 DGEDQTQDTELVETRPAGD 95.00% 92.6 35.4 244 262 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 NTQIYKAQAQTDRES 95.00% 56.4 40.2 87 101 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 GPEYWDRNTQIYKAQA 94.80% 55.6 39.9 80 95 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 YWDRNTQIYKAQAQT 94.70% 55.4 40.2 83 97 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 EGPEYWDRNTQIYKAQAQT 94.30% 54.4 39.9 79 97 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 RNTQIYKAQAQ 93.20% 51.6 39.8 86 96 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 TQIYKAQAQT 91.10% 47.2 40.7 88 97 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 GPEYWDRNTQIYKAQAQTDRESL 95.00% 45.7 40.8 80 102 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 DRNTQIYKAQAQTDRES 95.00% 58.4 40.6 85 101 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 EGPEYWDRNTQIYKAQAQTD 95.00% 57.4 38.7 79 98 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 GPEYWDRNTQIYKAQAQ 95.00% 61.3 40.4 80 96 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 GPEYWDRNTQIYKAQAQTD 95.00% 65.4 39.3 80 98 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 GPEYWDRNTQIYKAQAQT 95.00% 63.8 39.9 80 97 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00004657 TQIYKAQAQTDRES 88.10% 45.3 40.8 88 101 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 IALNEDLRSWTAADTAAQ 95.00% 106 41.1 148 165 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 DLRSWTAADTAAQITQ 95.00% 100 40.4 153 168 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 EDLRSWTAADTAAQITQ 95.00% 91.9 39.9 152 168 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 IALNEDLRSWTAADT 95.00% 86.6 40.4 148 162 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 DLRSWTAADTAAQIT 95.00% 76.7 40.6 153 167 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 IALNEDLRSWTAADTA 95.00% 74.8 40.2 148 163 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 EDLRSWTAADTAAQIT 95.00% 73 39.9 152 167 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 TAADTAAQITQRKLEAARA 95.00% 66.1 41.4 158 179 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 TAADTAAQITQRKLEAARA 95.00% 62.7 40 158 180 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 IALNEDLRSWTAAD 95.00% 61.9 39.3 148 161 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 EDLRSWTAADTAAQITQR 95.00% 60.7 40.5 152 169 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 IALNEDLRSWTAADTAA 95.00% 59.6 40.3 148 164 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 EDLRSWTAADTAAQITQRK 95.00% 58.7 40.9 152 170 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 ADTAAQITQRKLEAARAAEQL 95.00% 58 40.2 160 180 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 DTAAQITQRKLEAARAAEQL 95.00% 57.1 39.8 161 180 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 AADTAAQITQRKLEAARAAEQ 92.00% 51 41.3 159 179 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 KLEAARAAEQLR 95.00% 50 36 170 181 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 KLEAARAAEQ 95.00% 65.1 40.3 170 179 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 DGEDQTQDTELVETRPAGDG 95.00% 94.5 34.8 244 263 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 DGEDQTQDTELVETRPAGD 95.00% 92.6 35.4 244 262 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 DQTQDTELVETRPAGDG 95.00% 83 37.7 247 263 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00642409 TQDTELVETRPAGDG 95.00% 69.2 39.4 249 263 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 TQDTELVETRPAGDG 95.00% 69.2 39.4 249 263 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DQTQDTELVETRPAGDG 95.00% 83 37.7 247 263 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DGEDQTQDTELVETRPAGDG 95.00% 94.5 34.8 244 263 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DGEDQTQDTELVETRPAGD 95.00% 92.6 35.4 244 262 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 NEDLRSWTAADMAAQITKR 95.00% 88.3 41.2 151 169 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 EDLRSWTAADMAAQITKR 95.00% 102 41.3 152 169 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DLRSWTAADMAAQ 95.00% 80.9 37.2 153 165 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 EDLRSWTAADMAAQ 95.00% 75.6 37.3 152 165 Diabetes Page 38 of 49

LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DLRSWTAADMAAQITK 95.00% 75.2 40.8 153 168 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 EDLRSWTAADMAAQITK 95.00% 74.9 40.7 152 168 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 LRSWTAADMAAQIT 95.00% 64.2 39.8 154 167 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DLRSWTAADMAAQIT 95.00% 64.1 40.1 153 167 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DLRSWTAADMAAQITKR 95.00% 63.8 40.8 153 169 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 IALNEDLRSWTAAD 95.00% 61.9 39.3 148 161 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 EDLRSWTAADMAAQIT 95.00% 61.5 39.4 152 167 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 EDLRSWTAADMAAQITKRK 95.00% 57.5 41.3 152 170 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 WDQETRNVKAQSQTDRVD 94.90% 56.5 40.7 84 101 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 GPEYWDQETRNVKAQSQTDR 95.00% 55.4 39.1 80 99 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 GPEYWDQETRNVKAQSQTDRVD 94.70% 54.7 39.4 80 101 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 EGPEYWDQETRNVKAQSQTDR 94.00% 52.2 38.5 79 99 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DQETRNVKAQSQTD 93.00% 50.4 38.8 85 98 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DQETRNVKAQSQTDR 92.30% 50.4 40.3 85 99 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457EGPEYWDQETRNVKAQSQTDRVD 95.00% 57.7 38.6 79 101 LOC441528;XXbac-BPG181B23.1;MICA;LOC100133382;HLA-A;HLA-B;HLA-C;LIPI00647457 DQETRNVKAQSQTDRVD 88.50% 45.2 40.4 85 101 LOC442497;SLC3A2 4F2 cell-surface antigen heavy chain IPI00027493 QPMNAASGAAMSLAGAE 95.00% 86.8 37.7 123 139 LOC442497;SLC3A2 4F2 cell-surface antigen heavy chain IPI00027493 EPEKQPMNAASGAAMSLAGAE 95.00% 80.6 38.7 119 139 LOC442497;SLC3A2 4F2 cell-surface antigen heavy chain IPI00027493 QPMNAASGAAMSLAG 95.00% 72.4 37.6 123 137 LOC442497;SLC3A2 4F2 cell-surface antigen heavy chain IPI00027493 EPEKQPMNAASGAAMS 95.00% 65.4 37 119 134 LOC442497;SLC3A2 4F2 cell-surface antigen heavy chain IPI00027493 EPEKQPMNAASGAAMSLAG 95.00% 48.3 39 119 137 LOC729708;LOC388642 Triosephosphate isomerase (Fragment) IPI00383071 GFLVGGASLKPEFVD 95.00% 52.7 38.6 190 204 LRIG3 Isoform 1 of Leucine-rich repeats and immunoglobulin-like domains proteinIPI00184265 DAEMENYAHLRAQGGEV 95.00% 67 37 483 499 LRP6 Low-density lipoprotein receptor-related protein 6 IPI00000203 AIPLTGVKEASALDFD 95.00% 90.8 40.6 655 670 LSR Isoform 1 of Lipolysis-stimulated lipoprotein receptor IPI00409640 DTDSSVASEVRSGYRIQ 88.20% 45.3 39.9 359 375 LYN Isoform LYN A of Tyrosine-protein kinase Lyn IPI00298625 APGNSAGAFLIRESETLK 95.00% 89 40.1 215 232 LYN Isoform LYN A of Tyrosine-protein kinase Lyn IPI00298625 APGNSAGAFLIRESE 95.00% 86.3 39.6 215 229 LYN Isoform LYN A of Tyrosine-protein kinase Lyn IPI00298625 APGNSAGAFLIRESETL 95.00% 77.2 40.6 215 231 LYN Isoform LYN A of Tyrosine-protein kinase Lyn IPI00298625 APGNSAGAFLIRESET 95.00% 75.2 40.5 215 230 MAN1A1 MAN1A1 protein IPI00439446 NIKGATIVDALDTL 95.00% 92.7 38.9 235 248 MAN1A1 MAN1A1 protein IPI00439446 NIKGATIVDALDT 95.00% 87.2 41.3 235 247 MAN1A1 MAN1A1 protein IPI00439446 IKGATIVDALDTL 95.00% 80 39.1 236 248 MAN1A1 MAN1A1 protein IPI00439446 FGNIKGATIVDALDTL 95.00% 78.5 39.8 233 248 MAN1A1 MAN1A1 protein IPI00439446 NIKGATIVDALD 95.00% 78.2 40.9 235 246 MAN1A1 MAN1A1 protein IPI00439446 GNIKGATIVDALDTL 95.00% 72.3 40.1 234 248 MAN1A1 MAN1A1 protein IPI00439446 FGNIKGATIVDALDT 95.00% 68.3 40.3 233 247 MAN1A1 MAN1A1 protein IPI00439446 IKGATIVDALDT 95.00% 63.2 40 236 247 MAN1A1 MAN1A1 protein IPI00439446 GNIKGATIVDALDT 95.00% 57.4 41 234 247 MAN1A1 MAN1A1 protein IPI00439446 GNIKGATIVDALD 95.00% 54.2 41.3 234 246 MAN1A1 MAN1A1 protein IPI00439446 FGNIKGATIVDALD 95.00% 53.1 40.2 233 246 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 WVMNDEAATHYGAIVDQ 95.00% 65.1 36.7 155 171 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 WVMNDEAATHYGAIVD 95.00% 64.8 37 155 170 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 DRSQGGSSLRDGSLE 95.00% 57.2 38.9 796 810 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 RSQGGSSLRDGSLE 95.00% 79.5 39.3 797 810 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 TDRSQGGSSLRDGSLE 95.00% 64.7 39.1 795 810 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 APLNEAMAVLQHHDA 95.00% 60 39.5 434 448 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 LDKLIRLVNAQQAKG 95.00% 58.4 33.3 332 346 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 LDKLIRLVNAQQAKGSS 95.00% 54.6 35.2 332 348 MAN2B1 Lysosomal alpha-mannosidase IPI00012989 ETTLVANQLREAASRLK 93.40% 50.4 38 953 969 MAP1LC3B2 Microtubule-associated proteins 1A/1B light chain 3B-like protein IPI00151462 LVNGHSMVSVSTPISE 95.00% 53.6 39.4 82 97 MARCKSL1 MARCKS-related protein IPI00641181 EPQAKGAEASAASEEEAGPQ 95.00% 97.4 37.8 153 172 MARCKSL1 MARCKS-related protein IPI00641181 EPQAKGAEASAASEEEA 95.00% 90.5 37.5 153 169 MARCKSL1 MARCKS-related protein IPI00641181 EPQAKGAEASAASEE 95.00% 87.4 36.6 153 167 MARCKSL1 MARCKS-related protein IPI00641181 EPQAKGAEASAASEEE 95.00% 82.7 37.1 153 168 MARCKSL1 MARCKS-related protein IPI00641181 AEEAAGASPAKANGQE 95.00% 75.3 36.6 15 30 MDH1 Malate dehydrogenase, cytoplasmic IPI00291005 GEFVTTVQQRGAAVI 95.00% 73.5 39.3 221 235 MDH1 Malate dehydrogenase, cytoplasmic IPI00291005 IIWGNHSSTQYPDVN 95.00% 51.8 39.3 182 196 MFGE8 Lactadherin IPI00002236 NGNIANSQIAASSVR 95.00% 107 39.4 78 92 MFGE8 Lactadherin IPI00002236 EVTGIITQGARN 95.00% 54 39.8 298 309 MFGE8 Lactadherin IPI00002236 SSKEVTGIITQGARNFG 95.00% 84.5 40.5 295 311 MFGE8 Lactadherin IPI00002236 SSKEVTGIITQGARNFGS 93.20% 52.2 40.2 295 312 MFSD2 Isoform 1 of Major facilitator superfamily domain-containing protein 2 IPI00410391 LGTVLGTAIQGQIVG 95.00% 63.2 37.9 190 204 MFSD2 Isoform 1 of Major facilitator superfamily domain-containing protein 2 IPI00410391 GTVLGTAIQGQIVG 95.00% 50.1 39.9 191 204 MFSD2 Isoform 1 of Major facilitator superfamily domain-containing protein 2 IPI00410391 LGTVLGTAIQGQIV 95.00% 45.8 36.4 190 203 MICAL3 Isoform 1 of Protein MICAL-3 IPI00177937 SGVNGLEEPSIAK 90.40% 47.5 41.4 733 745 MITD1 MIT domain-containing protein 1 IPI00103065 DPQSTAAATVLKRAVE 95.00% 65.7 39.9 9 24 MREG Isoform 1 of Melanoregulin IPI00017515 NPYSSFGATLVRDDEKN 90.10% 46.9 40 35 51 MRPL4 Isoform 1 of 39S ribosomal protein L4, mitochondrial IPI00023334 AEVRGGGRKPWP 95.00% 48.4 38.8 118 129 MS4A1 B-lymphocyte antigen CD20 IPI00007880 SKTLGAVQIMNGLF 95.00% 75.1 39.1 49 62 MS4A1 B-lymphocyte antigen CD20 IPI00007880 ESKTLGAVQIMNGLFH 93.20% 53 41.1 48 63 Page 39 of 49 Diabetes

MTHFD1 C-1-tetrahydrofolate synthase, cytoplasmic IPI00218342 EEVINAIAPEKDVDG 95.00% 56.8 40.4 151 165 MVP Major vault protein IPI00000105 VVEIIQATIIRQNQ 95.00% 86.1 36 159 172 MVP Major vault protein IPI00000105 VVEIIQATIIRQN 95.00% 76.6 35.5 159 171 MVP Major vault protein IPI00000105 IIQATIIRQNQ 95.00% 72.6 36.4 162 172 MVP Major vault protein IPI00000105 VVEIIQATIIRQNQA 95.00% 66.9 36.3 159 173 MVP Major vault protein IPI00000105 VVEIIQATIIRQNQAL 95.00% 62.7 34.6 159 174 MVP Major vault protein IPI00000105 VEIIQATIIRQNQ 95.00% 60.1 37 160 172 MVP Major vault protein IPI00000105 IPLDENEGIYVQDVKTG 95.00% 107 40.9 380 396 MVP Major vault protein IPI00000105 DENEGIYVQDVK 95.00% 71.6 39.1 383 394 MVP Major vault protein IPI00000105 IPLDENEGIYVQDVKTGK 95.00% 60 41.2 380 397 MYH9 Myosin-9 IPI00019502 DPLNDNIATLLHQSSDK 95.00% 62.9 40.6 590 606 MYH9 Myosin-9 IPI00019502 QAQIAELKMQLAKKEEE 91.20% 49.5 41 1068 1084 NAPA Alpha-soluble NSF attachment protein IPI00009253 EQYQKAIDIYEQVGTN 95.00% 68.4 40 176 191 NAPA Alpha-soluble NSF attachment protein IPI00009253 EQYQKAIDIYEQVG 95.00% 56.1 40 176 189 NBR1 neighbor of BRCA1 gene 1 IPI00783855 LDEENEEVSINSQGEYE 95.00% 121 33.2 49 65 NBR1 neighbor of BRCA1 gene 1 IPI00783855 LDEENEEVSINSQGEY 95.00% 96.5 34.8 49 64 NBR1 neighbor of BRCA1 gene 1 IPI00783855 EDQTAALMAHLFE 95.00% 73.3 38 914 926 NDFIP2 NEDD4 family-interacting protein 2 IPI00385038 LNEEDNSESSAIEQPP 95.00% 94 36.2 109 124 NDFIP2 NEDD4 family-interacting protein 2 IPI00385038 EEDNSESSAIEQPP 95.00% 91.6 34.3 111 124 NDFIP2 NEDD4 family-interacting protein 2 IPI00385038 EDNSESSAIEQPP 95.00% 56.5 34.5 112 124 NDFIP2 NEDD4 family-interacting protein 2 IPI00385038 NPAPQIVQAASSAPALETD 95.00% 65.8 40.8 127 145 NDFIP2 NEDD4 family-interacting protein 2 IPI00385038 NPAPQIVQAASSAPALE 95.00% 64.1 40.9 127 143 NECAP2 Isoform 1 of Adaptin ear-binding coat-associated protein 2 IPI00018188 STGSTSSQTQPGTGWVQ 95.00% 92.6 38.1 246 262 NECAP2 Isoform 1 of Adaptin ear-binding coat-associated protein 2 IPI00018188 STGSTSSQTQPGTGWV 95.00% 74.9 38.2 246 261 NECAP2 Isoform 1 of Adaptin ear-binding coat-associated protein 2 IPI00018188 QLAVGGSLVQPAVAPS 95.00% 47.9 38.5 206 221 NECAP2 Isoform 1 of Adaptin ear-binding coat-associated protein 2 IPI00018188 LAVGGSLVQPAVAPS 94.90% 47.1 38.2 207 221 NEDD1 Protein NEDD1 IPI00169345 DAVVNKGSDESIGKGDG 95.00% 56 39.6 60 76 NEDD4L Isoform 4 of E3 ubiquitin-protein ligase NEDD4-like protein IPI00023287 VPMNGFAELYGSNGPQ 95.00% 70 38.5 880 895 NEU1 Sialidase-1 IPI00029817 SDEGAKFIALRRSMDQG 91.40% 49.4 40.7 102 118 NID1 Isoform 1 of Nidogen-1 IPI00026944 ENNQVPAVVAFSQGSV 95.00% 73.3 40.5 211 226 NID1 Isoform 1 of Nidogen-1 IPI00026944 ENNQVPAVVAFSQGSVG 95.00% 53.3 40.4 211 227 NID1 Isoform 1 of Nidogen-1 IPI00026944 EDLSPSITQRAAE 95.00% 65.4 40.7 124 136 NID1 Isoform 1 of Nidogen-1 IPI00026944 ENTDLHSYVVMNHGRSY 95.00% 64.8 38.1 454 470 NID1 Isoform 1 of Nidogen-1 IPI00026944 NTDLHSYVVMNHGRSY 94.90% 54.8 38.9 455 470 NID1 Isoform 1 of Nidogen-1 IPI00026944 TDLHSYVVMNHGRS 93.60% 52.3 39.5 456 469 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 DALLGQVKASLLPGGSEGGR 95.00% 92.1 39.8 1643 1662 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 LGQVKASLLPGGSEG 95.00% 84.6 39.6 1646 1660 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 LGQVKASLLPGGSE 95.00% 72.4 39.8 1646 1659 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 LGQVKASLLPGGSEGG 95.00% 69.2 39.6 1646 1661 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 DPMDVRGSIVY 95.00% 69.9 38.6 1668 1678 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 VDDLGKSALHWAAAVN 95.00% 74.6 40.6 2025 2040 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 AVDDLGKSALHWAAAVN 95.00% 68.5 40.8 2024 2040 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 DDLGKSALHWAAAVN 95.00% 53.6 40.9 2026 2040 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 VGPLHSSLAASALSQ 95.00% 81.4 39.2 2348 2362 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 GPLHSSLAASALSQM 95.00% 68.4 40.5 2349 2363 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 APAVISDFIYQGASLHNQTDRTG 95.00% 92.4 41.2 1907 1929 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 SDFIYQGASLHNQTD 95.00% 86.8 37.6 1912 1926 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 APAVISDFIYQGASLHNQTDR 95.00% 63.2 40.8 1907 1927 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 SDFIYQGASLHNQTDRT 93.80% 52.9 39.6 1912 1928 NOTCH1 Neurogenic locus notch homolog protein 1 IPI00412982 SDFIYQGASLHNQTDR 90.40% 46.8 39.6 1912 1927 NPEPPS Puromycin-sensitive aminopeptidase IPI00026216 GKLEAAAQVRQATNQ 90.50% 46.2 38.9 78 92 NUCB1 Nucleobindin-1 IPI00295542 LLIQTATRDLAQYDAAHH 95.00% 68.3 41.1 156 173 NUCB1 Nucleobindin-1 IPI00295542 LLIQTATRDLAQYDAA 95.00% 62.5 40.1 156 171 NUP210 Isoform 1 of Nuclear pore membrane glycoprotein 210 IPI00291755 DIGFSVIQAHDVQ 95.00% 85.2 38.6 508 520 OPTN Isoform 1 of Optineurin IPI00304189 EDLETMTILRAQ 95.00% 61.5 42.1 456 467 OPTN Isoform 1 of Optineurin IPI00304189 EEDLETMTILRAQ 95.00% 97.8 40.9 455 467 OPTN Isoform 1 of Optineurin IPI00304189 QEEDLETMTILRAQ 95.00% 68.5 40 454 467 OPTN Isoform 1 of Optineurin IPI00304189 SSEDSFVEIRMAEGEA 95.00% 66.3 36.2 173 188 OPTN Isoform 1 of Optineurin IPI00304189 ESMLSEIKMEQAKTED 95.00% 62.8 38.9 366 381 OPTN Isoform 1 of Optineurin IPI00304189 ESMLSEIKMEQAKTEDE 95.00% 58.1 37.5 366 382 OPTN Isoform 1 of Optineurin IPI00304189 ESMLSEIKMEQAKTEDEK 90.50% 47 39.6 366 383 PAFAH1B1 Isoform 1 of Platelet-activating factor acetylhydrolase IB subunit alph IPI00218728APESSYSSISEATGSETKKSGKPGP 95.00% 76.1 40.7 284 308 PAFAH1B1 Isoform 1 of Platelet-activating factor acetylhydrolase IB subunit alph IPI00218728 APESSYSSISEATGSE 95.00% 56.8 35.1 284 299 PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 VIDPNNAAVLQSSGKNL 95.00% 81.4 39.5 454 470 PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 VIDPNNAAVLQSSGKN 95.00% 77.5 40.2 454 469 PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 PNNAAVLQSSGKN 95.00% 70 38 457 469 PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 IDPNNAAVLQSSGKN 95.00% 107 39.5 455 469 PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 IDPNNAAVLQSSGKNL 95.00% 67.5 39.3 455 470 PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 WGEESSGSSPLPGQFT 95.00% 69.1 37.2 562 577 PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 WGEESSGSSPLPGQ 95.00% 84.7 35.9 562 575 Diabetes Page 40 of 49

PAM peptidylglycine alpha-amidating monooxygenase isoform a, preproprotein IPI00177543 GEESSGSSPLPGQFT 95.00% 64.4 37.5 563 577 PCBP1 Poly(rC)-binding protein 1 IPI00016610 EIRESTGAQVQVAGDM 95.00% 95.3 39.9 122 137 PCBP1 Poly(rC)-binding protein 1 IPI00016610 IRESTGAQVQVAGDM 95.00% 91.3 40.6 123 137 PCBP1 Poly(rC)-binding protein 1 IPI00016610 EIRESTGAQVQ 94.80% 49.2 40.4 122 132 PCBP1 Poly(rC)-binding protein 1 IPI00016610 EESGARINISEGN 95.00% 61.8 38.7 41 53 PCBP1 Poly(rC)-binding protein 1 IPI00016610 RQQSHFAMMHGGTG 94.70% 51.7 36.2 243 256 PCBP1 Poly(rC)-binding protein 1 IPI00016610 ARQQSHFAMMHGGTG 93.90% 48.7 35.3 242 256 PDCD6 Programmed cell death protein 6 IPI00025277 SGVISDTELQQALSN 95.00% 104 40.8 49 63 PDCD6 Programmed cell death protein 6 IPI00025277 SGVISDTELQQALS 95.00% 57.7 41 49 62 PDIA6 Isoform 2 of Protein disulfide-isomerase A6 IPI00299571 EPEWAAAASEVKEQTKG 95.00% 84.5 40.2 197 213 PDLIM1 PDZ and LIM domain protein 1 IPI00010414 TNQYNNPAGLYSSENIS 95.00% 92.5 37.3 141 157 PDXDC1 Isoform 1 of Pyridoxal-dependent decarboxylase domain-containing proIPI00384689 GIQEAQVELQKASEER 93.10% 51.8 40.1 616 631 PGK1 Phosphoglycerate kinase 1 IPI00169383 DEEGAKIVKDLMS 95.00% 58.6 40.5 259 271 PGK1 Phosphoglycerate kinase 1 IPI00169383 KELNYFAKALESPERP 95.00% 69.3 40.4 192 207 PGK1 Phosphoglycerate kinase 1 IPI00169383 ELNYFAKALESPERP 92.60% 51.5 40.8 193 207 PGK1 Phosphoglycerate kinase 1 IPI00169383 KELNYFAKALESPERPF 92.30% 50.7 40.5 192 208 PIK3IP1 Isoform 1 of Phosphoinositide-3-kinase-interacting protein 1 IPI00298388 LPARSEAAAVQPVIGIS 95.00% 46.6 36.7 137 153 PKM2 Isoform M1 of Pyruvate kinase isozymes M1/M2 IPI00220644 DLRVNFAMNVGKARG 94.10% 53.7 39.9 299 313 PLA1A Isoform 1 of Phospholipase A1 member A IPI00642790 TDTDNLGIRIPVGHVDY 95.00% 63.4 41.1 218 234 PLA1A Isoform 1 of Phospholipase A1 member A IPI00642790 TDTDNLGIRIPVGHVD 93.50% 53.4 41 218 233 PLD1 Isoform PLD1A of Phospholipase D1 IPI00012865 NEPVQNLPIQKSIDDVD 95.00% 70.5 40.4 529 545 PLEKHB2 Isoform 1 of Pleckstrin homology domain-containing family B member IPI00335457 LGMLAGAATGMALGSL 95.00% 127 39.4 202 217 PLEKHB2 Isoform 1 of Pleckstrin homology domain-containing family B member IPI00335457 LGMLAGAATGMALGS 95.00% 88.9 39.4 202 216 PLOD1 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 IPI00027192 IYLIKGSALRGELQ 95.00% 67.3 36.1 454 467 PLOD1 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 IPI00027192 SDQLFYTKIFLDPEKRE 95.00% 64.7 41.5 178 194 PLOD1 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 IPI00027192 DSDQLFYTKIFLDPEKRE 95.00% 57.7 41.4 177 194 PLSCR1 Phospholipid scramblase 1 IPI00005181 LSQIDQILIHQQIE 95.00% 77 39.1 85 98 PLSCR1 Phospholipid scramblase 1 IPI00005181 SQIDQILIHQQIE 95.00% 69.7 40.2 86 98 PLSCR1 Phospholipid scramblase 1 IPI00005181 QIDQILIHQQIE 95.00% 64.1 39.7 87 98 PLSCR1 Phospholipid scramblase 1 IPI00005181 FFESTGSQEQKSG 95.00% 64.4 36.6 287 299 PLTP 45 kDa protein IPI00022733 NSLLDTVPVRSSVDE 95.00% 68.8 40.8 197 211 PLXNB2 Plexin B2 IPI00852623 TNLNKAMTLQEAEAFVG 95.00% 96.4 40.9 1117 1133 PLXNB2 Plexin B2 IPI00852623 TNLNKAMTLQEAEA 95.00% 72.1 40.2 1117 1130 PLXNB2 Plexin B2 IPI00852623 TNLNKAMTLQEAEAFV 95.00% 59.3 41.2 1117 1132 PLXNB2 Plexin B2 IPI00852623 TNLNKAMTLQEAEAF 95.00% 54.2 40.6 1117 1131 PLXNB2 Plexin B2 IPI00852623 LDTVKGSSLHVGSDL 95.00% 75.7 40.3 692 706 PLXNB2 Plexin B2 IPI00852623 NLDTVKGSSLHVGSDLL 95.00% 71 39 691 707 PLXNB2 Plexin B2 IPI00852623 NLDTVKGSSLHVGSDL 95.00% 66.9 40.2 691 706 PLXNB2 Plexin B2 IPI00852623 NLDTVKGSSLHVGSDLLK 95.00% 56.5 39.5 691 708 PLXNB2 Plexin B2 IPI00852623 LKFMEPVTMQESGTF 95.00% 56.4 38.9 707 721 PLXNB2 Plexin B2 IPI00852623 VVYLGAVNALYQLDAK 95.00% 63.3 39.1 45 60 PLXNB2 Plexin B2 IPI00852623 GPSPLVIPMNHETDVNFQGKN 89.30% 47.3 41.5 671 691 POU2AF1 POU domain class 2-associating factor 1 IPI00293727 SPPLITNVTTRSSATPA 95.00% 89.2 39.7 143 159 PPP2R1A cDNA FLJ34068 fis, clone FCBBF3001918, highly similar to SERINE/TIPI00168184 GPEITKTDLVPAFQ 93.70% 47.4 39.4 96 109 PPT1 Palmitoyl-protein thioesterase 1 IPI00002412 EMDNAGQLVFLATEGDH 95.00% 108 37.5 72 88 PSEN1 Isoform 1 of Presenilin-1 IPI00028077 RNETLFPALIYSST 95.00% 59.2 40.1 186 199 PSEN1 Isoform 1 of Presenilin-1 IPI00028077 NSKYNAESTERESQDTV 95.00% 57.6 37.2 220 236 PSEN1 Isoform 1 of Presenilin-1 IPI00028077 NSKYNAESTERESQDT 95.00% 53.5 35.5 220 235 PSMA5 Proteasome subunit alpha type-5 IPI00291922 ATNIELATVQPGQNFH 95.00% 68.7 40.6 212 227 PSMA5 Proteasome subunit alpha type-5 IPI00291922 NIELATVQPGQNFH 95.00% 66.4 40.5 214 227 PSMB10 Proteasome subunit beta type-10 IPI00027933 DGVILGADTRATNDS 95.00% 74.1 39.9 49 63 RAB11A Ras-related protein Rab-11A IPI00429190 FAEKNGLSFIETSALD 95.00% 64.1 40.7 142 157 RAB11A Ras-related protein Rab-11A IPI00429190 TSALDSTNVEAAFQ 95.00% 53.4 39.2 153 166 RAB11FIP1 Isoform 1 of Rab11 family-interacting protein 1 IPI00419433 GPGGTSDAYAVIQVGKEKY 95.00% 62.2 41 34 52 RAB11FIP1 Isoform 1 of Rab11 family-interacting protein 1 IPI00419433 GPGGTSDAYAVIQVGKEKYA 95.00% 57.9 41.2 34 53 RAB21 Ras-related protein Rab-21 IPI00007755 YRDSNGAILVYDITDE 95.00% 87.4 39.4 89 104 RAB21 Ras-related protein Rab-21 IPI00007755 RDSNGAILVYDITDE 95.00% 79.8 40 90 104 RAB21 Ras-related protein Rab-21 IPI00007755 RDSNGAILVYDITDED 95.00% 71.8 39 90 105 RAB21 Ras-related protein Rab-21 IPI00007755 YRDSNGAILVYDITD 95.00% 57.3 39.3 89 103 RAB4A RAB4A, member RAS oncogene family variant IPI00480056 KDDSNHTIGVEFGSKIIN 95.00% 87.8 41.2 39 56 RAB4A RAB4A, member RAS oncogene family variant IPI00480056 TNWLTDARMLASQN 95.00% 73 39.4 105 118 RAB4B Isoform 2 of Ras-related protein Rab-4B IPI00187143 AAWLTDARTLASPNIV 95.00% 59.4 40.1 100 115 RAB5C Ras-related protein Rab-5C IPI00016339 ADDNSLLFMETSAK 95.00% 117 38.4 153 166 RAB5C Ras-related protein Rab-5C IPI00016339 ADDNSLLFMETSAKT 95.00% 93.8 39.1 153 167 RAB5C Ras-related protein Rab-5C IPI00016339 ADDNSLLFMETSAKTA 95.00% 89.4 39.4 153 168 RAB5C Ras-related protein Rab-5C IPI00016339 DDNSLLFMETSAK 95.00% 87.1 38.8 154 166 RAB5C Ras-related protein Rab-5C IPI00016339 DDNSLLFMETSAKT 95.00% 79.3 38.4 154 167 RAB5C Ras-related protein Rab-5C IPI00016339 DDNSLLFMETSAKTA 95.00% 70.7 38.9 154 168 RAB8B Ras-related protein Rab-8B IPI00024282 IKNWIRNIEEHASSDVER 95.00% 57.2 41.1 99 116 RALB Ras-related protein Ral-B IPI00004397 AGQEDYAAIRDNYFR 90.00% 45.6 39 70 84 Page 41 of 49 Diabetes

RELT Tumor necrosis factor receptor superfamily member 19L IPI00064377 DANEDTIGVLVR 95.00% 69.1 41 218 229 RHBDF2 Isoform 1 of Rhomboid family member 2 IPI00433499 EPASSGAHIWPDD 95.00% 64.1 35.2 529 541 RHBDF2 Isoform 1 of Rhomboid family member 2 IPI00433499 EEPASSGAHIWPDD 95.00% 58.6 35 528 541 RHBDF2 Isoform 1 of Rhomboid family member 2 IPI00433499 EEPASSGAHIWPDDIT 95.00% 56.8 38.1 528 543 RHBDF2 Isoform 1 of Rhomboid family member 2 IPI00433499 EPASSGAHIWPDDIT 95.00% 56.8 38.9 529 543 RNF19A Isoform 1 of E3 ubiquitin-protein ligase RNF19A IPI00019056 DNASTKAMAGSIL 95.00% 92.7 40.2 558 570 RNF19A Isoform 1 of E3 ubiquitin-protein ligase RNF19A IPI00019056 VSDNASTKAMAGSILN 95.00% 77.3 41.1 556 571 RNF19A Isoform 1 of E3 ubiquitin-protein ligase RNF19A IPI00019056 SDNASTKAMAGSIL 95.00% 70 39.7 557 570 RNF19A Isoform 1 of E3 ubiquitin-protein ligase RNF19A IPI00019056 VSDNASTKAMAGSIL 95.00% 63.3 39.4 556 570 RNF19B Isoform 1 of E3 ubiquitin-protein ligase RNF19B IPI00477479 EAEAAAAAAEPGFDDEE 95.00% 82.1 31.8 89 105 RNF19B Isoform 1 of E3 ubiquitin-protein ligase RNF19B IPI00477479 AEAEAAAAAAEPGFDDEE 95.00% 73.3 31.9 88 105 RNF19B Isoform 1 of E3 ubiquitin-protein ligase RNF19B IPI00477479 ISDNASTRAMAGSIIS 95.00% 56.5 40.8 559 574 RPL9 60S ribosomal protein L9 IPI00031691 LVSNSAALIQQATTVK 95.00% 119 37.4 26 41 RPL9 60S ribosomal protein L9 IPI00031691 LVSNSAALIQQATTVKN 95.00% 96.1 38.2 26 42 RPL9 60S ribosomal protein L9 IPI00031691 LVSNSAALIQQATT 95.00% 94.8 40.5 26 39 RPL9 60S ribosomal protein L9 IPI00031691 LVSNSAALIQQAT 95.00% 85.3 40.9 26 38 RPL9 60S ribosomal protein L9 IPI00031691 LVSNSAALIQQATTV 95.00% 83.6 39.7 26 40 RPL9 60S ribosomal protein L9 IPI00031691 ELVSNSAALIQQATTVK 95.00% 79.5 38.8 25 41 RPS20 40S ribosomal protein S20 IPI00012493 IVKQITSISIEPGVE 95.00% 79.6 38.4 16 30 RPS20 40S ribosomal protein S20 IPI00012493 IVKQITSISIEPGVEVE 95.00% 67.7 37.2 16 32 S100A8 Protein S100-A8 IPI00007047 DINTDGAVNFQE 95.00% 83.6 38.3 59 70 S100A8 Protein S100-A8 IPI00007047 FKELDINTDGAVN 95.00% 81.5 40.6 55 67 S100A8 Protein S100-A8 IPI00007047 DINTDGAVN 95.00% 52.4 40.2 59 67 S100A8 Protein S100-A8 IPI00007047 DINTDGAVNFQ 95.00% 46.7 39.5 59 69 S100A8 Protein S100-A8 IPI00007047 MLTELEKALNS 95.00% 80.1 40.3 1 11 S100A8 Protein S100-A8 IPI00007047 MLTELEKAL 95.00% 58.6 37.1 1 9 S100A8 Protein S100-A8 IPI00007047 TELEKALNSIID 95.00% 51.8 39.4 3 14 S100A8 Protein S100-A8 IPI00007047 MLTELEKALN 95.00% 52.1 38.4 1 10 S100A8 Protein S100-A8 IPI00007047 NSIIDVYHKYS 95.00% 53.5 37.4 10 20 S100A9 Protein S100-A9 IPI00027462 DTNADKQLSFEE 95.00% 72.5 37.2 67 78 S100A9 Protein S100-A9 IPI00027462 LDTNADKQLS 95.00% 70.7 40.5 66 75 S100A9 Protein S100-A9 IPI00027462 DTNADKQLSF 95.00% 65.4 38.8 67 76 S100A9 Protein S100-A9 IPI00027462 DTNADKQLSFE 95.00% 61 37.6 67 77 S100A9 Protein S100-A9 IPI00027462 DLDTNADKQ 95.00% 60 39.3 65 73 S100A9 Protein S100-A9 IPI00027462 LDTNADKQL 95.00% 59 41.9 66 74 S100A9 Protein S100-A9 IPI00027462 LDTNADKQ 95.00% 53 41.6 66 73 S100A9 Protein S100-A9 IPI00027462 DTNADKQLS 95.00% 48.1 39.7 67 75 S100A9 Protein S100-A9 IPI00027462 DTNADKQL 95.00% 48 41.6 67 74 S100A9 Protein S100-A9 IPI00027462 LGHPDTLNQGEFK 95.00% 58.8 38.9 26 38 S100A9 Protein S100-A9 IPI00027462 SVKLGHPDTL 95.00% 53.6 39.6 23 32 S100A9 Protein S100-A9 IPI00027462 IINTFHQY 95.00% 67 38.8 15 22 S100A9 Protein S100-A9 IPI00027462 TIINTFHQY 95.00% 53.5 38.1 14 22 SCAMP2 Secretory carrier-associated membrane protein 2 IPI00218850 LPGSSQPAVLQPSVEPTQ 95.00% 91 40.7 54 71 SCAMP2 Secretory carrier-associated membrane protein 2 IPI00218850 LPGSSQPAVLQPSVEPTQPT 95.00% 79.7 40.9 54 73 SCAMP2 Secretory carrier-associated membrane protein 2 IPI00218850 LPGSSQPAVLQPSVEPT 95.00% 77 40.6 54 70 SCAMP2 Secretory carrier-associated membrane protein 2 IPI00218850 LPGSSQPAVLQPSVEPTQP 95.00% 66.9 40.9 54 72 SCAMP2 Secretory carrier-associated membrane protein 2 IPI00218850 LPGSSQPAVLQPSVE 95.00% 65 40.3 54 68 SCAMP2 Secretory carrier-associated membrane protein 2 IPI00218850 LPGSSQPAVLQPSVEPTQPTP 95.00% 60.8 40.8 54 74 SCAMP2 Secretory carrier-associated membrane protein 2 IPI00218850 LPGSSQPAVLQPSVEP 95.00% 59.1 40.8 54 69 SCARB1 Isoform 1 of Scavenger receptor class B member 1 IPI00177968 SAPKGSVLQEAKL 95.00% 58.7 39.4 462 474 SCPEP1 Isoform 1 of Retinoid-inducible serine carboxypeptidase IPI00012426 IFSESYGGKMAAGIGLE 95.00% 77.2 40.6 163 179 SCPEP1 Isoform 1 of Retinoid-inducible serine carboxypeptidase IPI00012426 TDGVNFYNILTKSTPT 95.00% 62.1 40.8 264 279 SDCBP Syntenin-1 IPI00299086 VIQAQTAFSANPANPAIL 95.00% 89.7 39.9 15 32 SDCBP Syntenin-1 IPI00299086 IQAQTAFSANPANPAIL 95.00% 68.6 38.8 16 32 SDF4 45 kDa calcium-binding protein IPI00106646 YNALNEAKQMIAVADEN 95.00% 81.1 39.8 313 329 SDF4 45 kDa calcium-binding protein IPI00106646 DPMNEYNALNEAKQ 95.00% 97.7 37 308 321 SDF4 45 kDa calcium-binding protein IPI00106646 MDPMNEYNALNEAKQM 95.00% 89.3 34.5 307 322 SDF4 45 kDa calcium-binding protein IPI00106646 DPMNEYNALNEAKQM 95.00% 84.5 36.1 308 322 SDF4 45 kDa calcium-binding protein IPI00106646 MDPMNEYNALNEAKQ 95.00% 82.3 35.5 307 321 SDF4 45 kDa calcium-binding protein IPI00106646 YNALNEAKQMIAVADENQNHH 95.00% 58.3 39.7 313 333 SDF4 45 kDa calcium-binding protein IPI00106646 NALNEAKQMIAVADENQNHH 89.30% 45.5 39.7 314 333 SEMA4A Semaphorin-4A IPI00149097 LPFNVIRHAVLLPADSPTAPH 93.60% 51.4 38.7 167 187 SEMA4A Semaphorin-4A IPI00149097 LPFNVIRHAVLLPADSPT 92.30% 47.9 37.7 167 184 SEMA4D Semaphorin-4D IPI00023807 EPSFVFADVIRKSPDSPDGEDDR 95.00% 65.1 39.8 208 230 SEMA4D Semaphorin-4D IPI00023807 EPSFVFADVIRKSPDSPDG 95.00% 64.3 40.4 208 226 SEMA4D Semaphorin-4D IPI00023807 EPSFVFADVIRKSPDSPD 95.00% 60 41 208 225 SEMA4D Semaphorin-4D IPI00023807 EPSFVFADVIRKSPDSP 95.00% 50.5 40.9 208 224 SEMA7A Semaphorin-7A IPI00025257 NPQFIKATIVHQDQAYD 95.00% 70.2 40.5 221 237 SEMA7A Semaphorin-7A IPI00025257 NPQFIKATIVHQDQAYDD 95.00% 67.2 40.4 221 238 SEMA7A Semaphorin-7A IPI00025257 NPQFIKATIVHQDQAYDDK 92.00% 51 41.3 221 239 Diabetes Page 42 of 49

SGCE sarcoglycan, epsilon isoform 1 IPI00414984 GDFLGAVKNVWQPER 95.00% 65.7 39.4 181 195 SGMS2 Phosphatidylcholine:ceramide cholinephosphotransferase 2 IPI00169331 QPSDPTNTYARPAEPVE 95.00% 67.2 39.6 16 32 SGTA Small glutamine-rich tetratricopeptide repeat-containing protein alpha IPI00013949 SPSQNDLASLIQAGQQ 95.00% 98.9 39.6 264 279 SILV Melanocyte protein Pmel 17 IPI00031630 DFGDSSGTLISRAL 95.00% 84.5 40.5 84 97 SILV Melanocyte protein Pmel 17 IPI00031630 DFGDSSGTLISRALVVT 95.00% 57.8 40.4 84 100 SLAMF6 SLAM family member 6 IPI00513714 SPTNNTVYASVTHSNRET 95.00% 66.2 39.3 277 294 SLC12A7 Isoform 1 of Solute carrier family 12 member 7 IPI00008616 LNGVVLNKSQDAQ 95.00% 73.1 40.1 1023 1035 SLC19A1 Folate transporter 1 IPI00375452 VDPTTNSARVYNGAAD 95.00% 81.9 38.7 295 310 SLC19A1 Folate transporter 1 IPI00375452 VDPTTNSARVYNGAADA 95.00% 79.9 39.2 295 311 SLC19A1 Folate transporter 1 IPI00375452 PTTNSARVYNGAADA 95.00% 58 39.9 297 311 SLC19A1 Folate transporter 1 IPI00375452 ASTLLGAITSFAAG 95.00% 52.9 40.3 312 325 SLC20A1 Sodium-dependent phosphate transporter 1 IPI00023035 DSTVNGAVQLPNGNL 95.00% 60.1 39.6 345 359 SLC2A6 Putative uncharacterized protein IPI00179969 VPSAAGYALMAGAHG 95.00% 110 39.1 117 131 SLC35F2 Isoform 1 of Solute carrier family 35 member F2 IPI00293362 EDNSGSDVLIGDIL 95.00% 99.2 40.3 188 201 SLC35F2 Isoform 1 of Solute carrier family 35 member F2 IPI00293362 REDNSGSDVLIGDIL 95.00% 93.7 40.8 187 201 SLC35F2 Isoform 1 of Solute carrier family 35 member F2 IPI00293362 GREDNSGSDVLIGDIL 95.00% 90.1 40.2 186 201 SLC35F2 Isoform 1 of Solute carrier family 35 member F2 IPI00293362 GVGTMVGADILAGREDN 95.00% 93.4 40.2 174 190 SLC35F2 Isoform 1 of Solute carrier family 35 member F2 IPI00293362 VGTMVGADILAGRED 95.00% 115 41.2 175 189 SLC35F2 Isoform 1 of Solute carrier family 35 member F2 IPI00293362 VGTMVGADILAGREDN 95.00% 114 40.6 175 190 SLC35F2 Isoform 1 of Solute carrier family 35 member F2 IPI00293362 TMVGADILAGREDN 95.00% 77.1 38.4 177 190 SLC38A2 Isoform 1 of Sodium-coupled neutral amino acid transporter 2 IPI00410034 TANEGGSLLYEQLGYK 95.00% 83.6 40.7 34 49 SLC38A2 Isoform 1 of Sodium-coupled neutral amino acid transporter 2 IPI00410034 TANEGGSLLYEQLG 95.00% 49.8 39.9 34 47 SLC38A5 Isoform 1 of Sodium-coupled neutral amino acid transporter 5 IPI00102509 DPKMNGALPSDAVGY 95.00% 83.3 38.5 5 19 SLC38A5 Isoform 1 of Sodium-coupled neutral amino acid transporter 5 IPI00102509 DPKMNGALPSDAVG 95.00% 63.1 38.1 5 18 SLC38A5 Isoform 1 of Sodium-coupled neutral amino acid transporter 5 IPI00102509 LQDPKMNGALPSDAVG 95.00% 62.8 40.3 3 18 SLC38A5 Isoform 1 of Sodium-coupled neutral amino acid transporter 5 IPI00102509 PKMNGALPSDAVG 95.00% 58.6 38.8 6 18 SLC38A5 Isoform 1 of Sodium-coupled neutral amino acid transporter 5 IPI00102509 QDPKMNGALPSDAVG 91.30% 46.5 39.9 4 18 SLC38A5 Isoform 1 of Sodium-coupled neutral amino acid transporter 5 IPI00102509 QDPKMNGALPSDAVGY 90.60% 45.7 39.4 4 19 SLC39A3 Isoform 1 of Zinc transporter ZIP3 IPI00029337 VPGSVASVLLQGLAGG 95.00% 65.2 37.7 353 368 SLC4A2 Isoform A of Anion exchange protein 2 IPI00383597 KGAQAGTQVEEAEAEA 95.00% 83.9 39.4 174 189 SLC4A2 Isoform A of Anion exchange protein 2 IPI00383597 TPRASKGAQAGTQVEEAEAEA 95.00% 59.6 41.1 169 189 SLC7A1 High affinity cationic amino acid transporter 1 IPI00027728 IIGTSSVARAWSAT 95.00% 56 39.8 122 135 SLC7A5 Large neutral amino acids transporter small subunit 1 IPI00008986 VTLQRNITLLNGVA 95.00% 47.8 35.8 44 57 SNX17 Sorting nexin-17 IPI00014219 SASDVHGNFAFEGIGDED 95.00% 66.3 33.1 452 469 SNX17 Sorting nexin-17 IPI00014219 SASDVHGNFAFEGIGDE 95.00% 57.8 35.3 452 468 SNX17 Sorting nexin-17 IPI00014219 ASDVHGNFAFEGIGDED 95.00% 55.7 33.5 453 469 SORL1 Sortilin-related receptor IPI00022608 ENQEVILEEVRDFQ 95.00% 93.5 40.1 288 301 SORL1 Sortilin-related receptor IPI00022608 SRENQEVILEEVRDFQ 95.00% 74.2 40.4 286 301 SORL1 Sortilin-related receptor IPI00022608 GADASATQAARSTDVA 95.00% 80.6 38.7 2122 2137 SORL1 Sortilin-related receptor IPI00022608 GADASATQAARSTDVAA 95.00% 53.6 38.6 2122 2138 SORL1 Sortilin-related receptor IPI00022608 GADASATQAARSTD 95.00% 65.6 35.5 2122 2135 SORL1 Sortilin-related receptor IPI00022608 DASATQAARSTDVA 95.00% 55.7 36.7 2124 2137 SORL1 Sortilin-related receptor IPI00022608 GADASATQAARSTDVAAVVVP 91.50% 47.9 41.1 2122 2142 SORL1 Sortilin-related receptor IPI00022608 NTLQGFSIPFRAADL 95.00% 70.2 40.3 195 209 SORL1 Sortilin-related receptor IPI00022608 NTLQGFSIPFRAAD 95.00% 69.6 39 195 208 SORL1 Sortilin-related receptor IPI00022608 NTLQGFSIPFRAADLL 95.00% 60.4 40 195 210 SORL1 Sortilin-related receptor IPI00022608 VIINSGLETVEALA 95.00% 77.3 38.4 825 838 SORL1 Sortilin-related receptor IPI00022608 QSRENQEVILEEVRDFQ 92.60% 51.3 40.5 285 301 SORL1 Sortilin-related receptor IPI00022608 VVHLLGSEQQSSVQ 95.00% 81.2 39.5 312 325 SORL1 Sortilin-related receptor IPI00022608 SEQQSSVQLWVSFGRKP 87.80% 46 41.8 318 334 SQSTM1 Isoform 1 of Sequestosome-1 IPI00179473 DPSKPGGNVEGATQSLAEQM 95.00% 83.7 38.7 208 227 SQSTM1 Isoform 1 of Sequestosome-1 IPI00179473 DPSKPGGNVEGATQSLAEQ 95.00% 82.9 39.7 208 226 STAM2 Isoform 1 of Signal transducing adapter molecule 2 IPI00290542 NPTYMNQNSNLQSATGT 95.00% 111 36.8 458 474 STAM2 Isoform 1 of Signal transducing adapter molecule 2 IPI00290542 NPTYMNQNSNLQSATGTT 95.00% 88.2 37 458 475 STAM2 Isoform 1 of Signal transducing adapter molecule 2 IPI00290542 LQSATGTTAYTQQMG 95.00% 66.8 39.3 468 482 STX12 Syntaxin-12 IPI00329332 ANVESSEVHVERATEQLQ 95.00% 81.7 40.3 244 261 STX12 Syntaxin-12 IPI00329332 ANVESSEVHVERATEQ 95.00% 87.6 39.5 244 259 STX12 Syntaxin-12 IPI00329332 LQQLQHSTNQLAKETN 95.00% 69.3 41 63 78 STX12 Syntaxin-12 IPI00329332 LQQLQHSTNQLAKETNEL 95.00% 83.1 40.7 63 80 STX12 Syntaxin-12 IPI00329332 LQQLQHSTNQLAKETNE 94.30% 55 40.6 63 79 STX7 Isoform 1 of Syntaxin-7 IPI00289876 IEANVENAEVHVQQAN 95.00% 109 40 206 221 STX7 Isoform 1 of Syntaxin-7 IPI00289876 ANVENAEVHVQQAN 95.00% 104 38.8 208 221 STX7 Isoform 1 of Syntaxin-7 IPI00289876 NVENAEVHVQQANQQ 95.00% 99.4 39.7 209 223 STX7 Isoform 1 of Syntaxin-7 IPI00289876 ANVENAEVHVQQANQQ 95.00% 88.8 40.2 208 223 STX7 Isoform 1 of Syntaxin-7 IPI00289876 IEANVENAEVHVQQ 95.00% 86.5 40.7 206 219 STX7 Isoform 1 of Syntaxin-7 IPI00289876 ANVENAEVHVQQANQQL 95.00% 79.8 40.8 208 224 STX7 Isoform 1 of Syntaxin-7 IPI00289876 ANVENAEVHVQQANQ 95.00% 76.9 39.2 208 222 STX7 Isoform 1 of Syntaxin-7 IPI00289876 ANVENAEVHVQQANQQLS 95.00% 74.4 40.8 208 225 STX7 Isoform 1 of Syntaxin-7 IPI00289876 VENAEVHVQQANQQ 95.00% 71.9 40.4 210 223 STX7 Isoform 1 of Syntaxin-7 IPI00289876 NVENAEVHVQQAN 95.00% 70.7 38.8 209 221 Page 43 of 49 Diabetes

STX7 Isoform 1 of Syntaxin-7 IPI00289876 NVENAEVHVQQANQQL 95.00% 66.6 40.7 209 224 STX7 Isoform 1 of Syntaxin-7 IPI00289876 IEANVENAEVHVQ 95.00% 61.4 39.9 206 218 STX7 Isoform 1 of Syntaxin-7 IPI00289876 NVENAEVHVQQANQ 95.00% 57.9 40.1 209 222 STX7 Isoform 1 of Syntaxin-7 IPI00289876 IFKDLGMMIHEQGDV 95.00% 53.9 40.3 188 202 SYNGR2 Synaptogyrin-2 IPI00013946 NPKDVLVGADSVRAAIT 95.00% 67.7 39.5 134 150 SYNGR2 Synaptogyrin-2 IPI00013946 NPKDVLVGADSVRAA 95.00% 58.8 38.7 134 148 TCEB1P3 similar to elongation factor SIII p15 subunit IPI00013109 VNETNEVNF 95.00% 50.4 38.3 54 62 TFG Protein TFG IPI00294619 GPPSAPAEDRSGTPD 95.00% 75.8 37.7 194 208 TFRC Transferrin receptor protein 1 IPI00022462 NPGGYVAYSKAATVTGKL 95.00% 106 40 215 232 TFRC Transferrin receptor protein 1 IPI00022462 NPGGYVAYSKAATVTGK 95.00% 105 40.2 215 231 TFRC Transferrin receptor protein 1 IPI00022462 NPGGYVAYSKAATVTG 95.00% 97.5 40 215 230 TFRC Transferrin receptor protein 1 IPI00022462 NPGGYVAYSKAATVTGKLV 95.00% 95.8 39.6 215 233 TFRC Transferrin receptor protein 1 IPI00022462 PGGYVAYSKAATVTG 95.00% 93.2 39.7 216 230 TFRC Transferrin receptor protein 1 IPI00022462 GGYVAYSKAATVTG 95.00% 79.9 39.2 217 230 TFRC Transferrin receptor protein 1 IPI00022462 ENPGGYVAYSKAATVTG 95.00% 62.8 40.5 214 230 TFRC Transferrin receptor protein 1 IPI00022462 NPGGYVAYSKAATVTGKLVH 93.50% 52.8 40.2 215 234 TFRC Transferrin receptor protein 1 IPI00022462 VDGDNSHVEMKLAVDEEENADN 95.00% 76.3 33.5 29 50 TFRC Transferrin receptor protein 1 IPI00022462 VDGDNSHVEMKLAVDEEEN 95.00% 74.7 35.9 29 47 TFRC Transferrin receptor protein 1 IPI00022462 VDGDNSHVEMKLAVDEE 95.00% 72.6 36.8 29 45 TFRC Transferrin receptor protein 1 IPI00022462 VDGDNSHVEMKLAVDEEE 94.80% 51.9 36.1 29 46 TFRC Transferrin receptor protein 1 IPI00022462 QDSNWASKVEKLT 94.00% 48.3 40.1 524 536 TFRC Transferrin receptor protein 1 IPI00022462 LPALLENLKLRKQNN 94.20% 46 32 709 723 TFRC Transferrin receptor protein 1 IPI00022462 DQARSAFSNLFGGEP 95.00% 92.8 39.3 3 17 TFRC Transferrin receptor protein 1 IPI00022462 TWTIQGAANALSGDV 91.30% 45.6 39 739 753 TGFB1 Transforming growth factor beta-1 IPI00000075 MNRPFLLLMATP 95.00% 53.6 40.6 253 264 TLN1 Talin-1 IPI00298994 QGLISAARMVAAATN 95.00% 90 38.2 2391 2405 TLN1 Talin-1 IPI00298994 GDLISATKAAAGKVGD 95.00% 88.5 40.4 2092 2107 TLN1 Talin-1 IPI00298994 GDLISATKAAAGKVG 95.00% 62.4 39.1 2092 2106 TLN1 Talin-1 IPI00298994 LGDLISATKAAAGKVG 95.00% 62.3 37.6 2091 2106 TLN1 Talin-1 IPI00298994 DLISATKAAAGKVG 95.00% 54.2 39 2093 2106 TLN1 Talin-1 IPI00298994 GDLISATKAAAGKVGDDPA 93.00% 52 40.5 2092 2110 TMED2 Transmembrane emp24 domain-containing protein 2 IPI00016608 EMINELAVAMTAVK 95.00% 127 40.8 47 60 TMED2 Transmembrane emp24 domain-containing protein 2 IPI00016608 EEMINELAVAMTAVK 95.00% 125 41.2 46 60 TMEM123 Isoform 1 of Porimin IPI00217366 HESAAMAASANIEN 95.00% 74.6 34.7 27 40 TMEM161A Transmembrane protein 161A IPI00301841 DEVQQTAARIAGALGG 95.00% 67.2 39.5 322 337 TMEM161A Transmembrane protein 161A IPI00301841 EVQQTAARIAGALG 95.00% 50.3 38.9 323 336 TMEM50A Transmembrane protein 50A IPI00000612 GCLGQTGARIW 95.00% 60.2 39.4 86 96 TMEM87A cDNA FLJ76697 IPI00171422 QEPNGNSKVNKAQEDD 93.00% 49.7 38.2 441 456 TMEM87B Isoform 1 of Transmembrane protein 87B IPI00783380 SVSNGTAKPATSENFD 95.00% 59.3 38.3 494 509 TNFAIP3 Tumor necrosis factor, alpha-induced protein 3 IPI00009448 THLINAAKLDEANLPK 93.80% 51.5 38.3 322 337 TNFAIP3 Tumor necrosis factor, alpha-induced protein 3 IPI00009448 THLINAAKLDEANLPKE 92.20% 50.4 40.4 322 338 TNFRSF21 Tumor necrosis factor receptor superfamily member 21 IPI00004413 LFEIIGVKSQEASQTL 95.00% 106 39.6 628 643 TNFRSF21 Tumor necrosis factor receptor superfamily member 21 IPI00004413 LFEIIGVKSQEASQT 95.00% 94.9 40.5 628 642 TNFRSF21 Tumor necrosis factor receptor superfamily member 21 IPI00004413 LFEIIGVKSQEASQ 95.00% 69.5 40.9 628 641 TNFSF9 Tumor necrosis factor ligand superfamily member 9 IPI00013301 SDPGLAGVSLTGGLS 95.00% 82.2 41.7 111 125 TNFSF9 Tumor necrosis factor ligand superfamily member 9 IPI00013301 AVSGARASPGSAASPR 94.10% 54.5 40.6 54 69 TNIP1 Isoform 2 of TNFAIP3-interacting protein 1 IPI00216616 SPEGAGALLRKQE 95.00% 80.4 39.3 442 454 TNIP1 Isoform 2 of TNFAIP3-interacting protein 1 IPI00216616 SPEGAGALLRKQ 95.00% 79.5 38 442 453 TNIP1 Isoform 2 of TNFAIP3-interacting protein 1 IPI00216616 SPEGAGALLRKQEL 95.00% 66.8 38.3 442 455 TNIP1 Isoform 2 of TNFAIP3-interacting protein 1 IPI00216616 SPEGAGALLRKQELVT 95.00% 66.6 37.3 442 457 TNIP1 Isoform 2 of TNFAIP3-interacting protein 1 IPI00216616 SPEGAGALLRKQELV 95.00% 60.4 37.1 442 456 TNIP1 Isoform 2 of TNFAIP3-interacting protein 1 IPI00216616 TELRQKLADLQKQVTDLE 93.10% 51.8 40.2 336 353 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 GDDEDSLSSAYIQRVNTE 95.00% 117 36.8 326 343 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 DEDSLSSAYIQRVNTE 95.00% 93.3 38.5 328 343 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 LENVADLVRPSP 95.00% 108 39.3 82 93 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 LTLENVADLVRPSP 95.00% 80.7 38.8 80 93 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 TLENVADLVRPSPLT 95.00% 75.1 38.8 81 95 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 ENVADLVRPSP 95.00% 73.8 39.8 83 93 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 TLENVADLVRPSP 95.00% 70.5 39.7 81 93 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 TLENVADLVRPSPL 95.00% 62.6 38.9 81 94 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 LENVADLVRPSPL 95.00% 58.4 38.5 82 94 TPP1 Isoform 1 of Tripeptidyl-peptidase 1 IPI00298237 LENVADLVRPSPLT 95.00% 57.5 38.8 82 95 TPT1 Tumor protein, translationally-controlled 1 IPI00009943 GPEGEGTESTVITGVDIVMNHH 95.00% 61.6 39.7 22 43 Tyrosine-protein kinase receptor IPI00884937 ATPLLMQALPMGALPQGP 95.00% 126 40.2 110 127 Tyrosine-protein kinase receptor IPI00884937 TPLLMQALPMGALPQGPMQ 95.00% 107 40.8 111 129 Tyrosine-protein kinase receptor IPI00884937 ATPLLMQALPMGALPQGPMQ 95.00% 104 41.2 110 129 Tyrosine-protein kinase receptor IPI00884937 TPLLMQALPMGALPQGPM 95.00% 103 40.6 111 128 Tyrosine-protein kinase receptor IPI00884937 ATPLLMQALPMGALPQGPM 95.00% 100 40.6 110 128 Tyrosine-protein kinase receptor IPI00884937 TPLLMQALPMGALPQGP 95.00% 91.6 40.1 111 127 Tyrosine-protein kinase receptor IPI00884937 TPLLMQALPMGALPQG 95.00% 87.9 40 111 126 Diabetes Page 44 of 49

Tyrosine-protein kinase receptor IPI00884937 TPLLMQALPMGALPQ 95.00% 81.5 39 111 125 Tyrosine-protein kinase receptor IPI00884937 MRMATPLLMQALPM 95.00% 62.4 40 107 120 Tyrosine-protein kinase receptor IPI00884937 MRMATPLLMQALP 95.00% 59.5 38.7 107 119 Tyrosine-protein kinase receptor IPI00884937 LMQALPMGALPQGP 95.00% 49 39.1 114 127 Tyrosine-protein kinase receptor IPI00884937 SKMRMATPLLMQA 90.10% 46.4 40.3 105 117 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 IPPDQQRLIFAGKQLED 92.50% 50.7 40.2 52 68 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 IPPDQQRLIFAGKQLEDG 94.00% 48.9 40.7 52 69 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 DYNIQKESTLHLVLR 95.00% 85.3 39.8 74 88 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 YNIQKESTLHLVLR 95.00% 79.6 38 75 88 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 EPSDTIENVKAKIQDKEGIPPDQ 92.90% 53 41.7 34 56 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 EPSDTIENVKAKIQDKEGIPPD 92.30% 51.7 41.5 34 55 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 EPSDTIENVKAKIQDKEGIPP 89.80% 47.3 40.9 34 54 UBC;UBB;RPS27A ubiquitin and ribosomal protein S27a precursor IPI00179330 EPSDTIENVKAKIQDK 89.00% 46.4 40.9 34 49 UBE2V2 Ubiquitin-conjugating enzyme E2 variant 2 IPI00019600 NGINNSSGMVDARS 95.00% 89 35.9 89 102 UBE2V2 Ubiquitin-conjugating enzyme E2 variant 2 IPI00019600 GINNSSGMVDARS 95.00% 85.3 36.6 90 102 UBQLN4 Ubiquilin-4 IPI00024502 NREANLQALIATGGDIN 95.00% 101 39.6 561 577 UBQLN4 Ubiquilin-4 IPI00024502 REANLQALIATGGDIN 95.00% 96.6 40.2 562 577 UFM1 Ubiquitin-fold modifier 1 IPI00010207 AIITNDGIGINPAQTAG 95.00% 56.9 40.1 49 65 UFM1 Ubiquitin-fold modifier 1 IPI00010207 IITNDGIGINPAQTA 93.80% 48.1 40.1 50 64 VASP Vasodilator-stimulated phosphoprotein IPI00301058 DAAQFAAGMASALE 95.00% 76.2 37.1 98 111 VCP Transitional endoplasmic reticulum ATPase IPI00022774 EAEKNAPAIIFIDEL 95.00% 68.6 40.9 292 306 VCP Transitional endoplasmic reticulum ATPase IPI00022774 EAEKNAPAIIFIDE 95.00% 65.9 40.9 292 305 VDAC1 Voltage-dependent anion-selective channel protein 1 IPI00216308 SAKVNNSSLIGLGYTQT 95.00% 76.2 40.1 202 218 VPS35 Vacuolar protein sorting-associated protein 35 IPI00018931 EDEISDSKAQLAAIT 95.00% 56.8 40.8 615 629 WBP2 WW domain-binding protein 2 IPI00032050 TPAAEAKAAEAAASAYYN 95.00% 106 38.6 171 188 WBP2 WW domain-binding protein 2 IPI00032050 TPAAEAKAAEAAASAYY 95.00% 84.2 39.8 171 187 WBP2 WW domain-binding protein 2 IPI00032050 TPAAEAKAAEAAASA 95.00% 82.1 40.8 171 185 WBP2 WW domain-binding protein 2 IPI00032050 TPAAEAKAAEAAASAY 95.00% 79.8 40.2 171 186 WBP2 WW domain-binding protein 2 IPI00032050 TPAAEAKAAEAAASAYYNPGN 95.00% 69.5 39.1 171 194 WBP2 WW domain-binding protein 2 IPI00032050 TPAAEAKAAEAAASAYYNPGN 95.00% 68.7 39.8 171 193 WBP2 WW domain-binding protein 2 IPI00032050 GPDVPSTPAAEAKAAEAAASA 95.00% 55.4 40.3 165 185 WBP2 WW domain-binding protein 2 IPI00032050DVPSTPAAEAKAAEAAASAYYNPGN 94.30% 53.8 39.4 165 194 WBP2 WW domain-binding protein 2 IPI00032050 GPDVPSTPAAEAKAAEAAA 95.00% 52.4 40.2 165 183 WBP2 WW domain-binding protein 2 IPI00032050 GPDVPSTPAAEAKAAEAA 95.00% 50.5 40.4 165 182 WWP2 NEDD4-like E3 ubiquitin-protein ligase WWP2 IPI00013010 LPSRDSSGTAVAPEN 95.00% 78.5 39.5 163 177 WWP2 NEDD4-like E3 ubiquitin-protein ligase WWP2 IPI00013010 ENKGSVVSGGELT 95.00% 71.4 41.1 126 138 YWHAE 14-3-3 protein epsilon IPI00000816 EDLVYQAKLAEQAE 95.00% 74.2 40.8 5 18 YWHAE 14-3-3 protein epsilon IPI00000816 EDLVYQAKLAEQAERYD 95.00% 62.4 40 5 21 YWHAE 14-3-3 protein epsilon IPI00000816 EDLVYQAKLAEQAER 91.20% 48.9 40.5 5 19 YWHAE 14-3-3 protein epsilon IPI00000816 DREDLVYQAKLAEQAERYD 90.50% 47.8 40.5 3 21 ZDHHC18 Palmitoyltransferase ZDHHC18 IPI00183979 IDNTGSSTYRPPP 95.00% 52 39.8 165 177 ZSWIM6 zinc finger, SWIM domain containing 6 IPI00015424 AAAAAAAAAAAAAA 95.00% 90.2 39.2 241 254 ZSWIM6 zinc finger, SWIM domain containing 6 IPI00015424 AAAAAAAAAAAAAAA 95.00% 74.5 38.6 241 255 ZSWIM6 zinc finger, SWIM domain containing 6 IPI00015424 AAAAAAAAAAAAAG 95.00% 54.7 38.8 248 261 Page 45 of 49 Diabetes

SUPPLEMENTAL FIGURE 1

3 0 p 1 3 0 p 2 3 0 p 3

2 0 2 0 2 0 %

1 0 1 0 1 0

0 0 0 DEKRHNQSTYGAVLIPFMWC DEKRHNQSTYGAVLIPFMWC DEKRHNQSTYGAVLIPFMWC

3 0 p 4 3 0 p 5 3 0 p 6

2 0 2 0 2 0 %

1 0 1 0 1 0

0 0 0 DEKRHNQSTYGAVLIPFMWC DEKRHNQSTYGAVLIPFMWC DEKRHNQSTYGAVLIPFMWC

3 0 p 7 3 0 p 8 4 0 p 9

3 0 2 0 2 0

% 2 0

1 0 1 0 1 0

0 0 0 DEKRHNQSTYGAVLIPFMWC DEKRHNQSTYGAVLIPFMWC DEKRHNQSTYGAVLIPFMWC

Amino acid distributions at the anchor and non-anchor positions within the peptide-binding groove of T1D protective DQ6. Amino acids with a frequency of 1.5 times higher compared to the same amino acids in the human proteome were considered as preferred residues. The frequencies of amino acids in the human proteome were adapter from the human assembly database Expert Protein Analysis System (ExPASy).

1

Diabetes Page 46 of 49

SUPPLEMENTAL FIGURE 2

A B C D

Competitive HLA-DQ peptide binding assays. To demonstrate peptide stealing from DQ8 by DQ6, binding of a test peptide is tested in 96-well plates plates coated with to DQ8 (A), DQ6 (B) or DQ6+DQ8 (C and D). Here, it is assumed that the test peptide can bind both DQ6 and DQ8 but with a preferential binding to DQ6 in the presence of DQ8. Below each representation of a DQ coated experimental well the expected outcome is shown by binding curves, with increasing concentrations of test peptide on the x-axis (log µM) and signal (count per minute; CPM) on the y-axis. Once a peptide binds to DQ, the indicator peptide is outcompeted resulting in a decreasing signal with increasing concentrations of test peptide. Subsequently, a typical S- shaped binding curve originates. Once a test peptide does not bind, the indicator peptide is not outcompeted, stays bound to the DQ molecule resulting in a stable signal giving rise to a horizontal binding curve. A and B. Binding of a test peptide to DQ8 and DQ6, respectively, resulting in the S-shaped curves. C. Binding of the test peptide to DQ6 in the presence of DQ8 using the DQ8 indicator. As the test peptide preferentially binds DQ6, the DQ8 indicator is not outcompeted resulting in the horizontal binding curve. D. As C, but using the DQ6 indicator. Here, the indicator peptide is outcompeted since the test peptide binds preferentially to DQ6. Once a test peptide preferentially binds DQ8, the expected binding curves in C and D will be the opposite.

2

Page 47 of 49 Diabetes

SUPPLEMENTAL FIGURE 3

Staining of EBV-BLCL with IVD12 and SPV-L3. Homozygous HLA-DQ6 (MGAR) and HLA-

DQ8 (BSM) EBV-BLCL were stained with APC-conjugated SPV-L3 or with unconjugated

IVD12 followed by staining with the secondary antibody GAM-PE. As control, MGAR and

BSM were also stained with GAM-PE. IVD12 was used as ascites and two dilutions were used,

namely 10x and 100x diluted. SPV-L3 recognizes both HLA-DQ6 and HLA-DQ8 expressed

on MGAR and BSM, respectively. IVD12 only recognizes HLA-DQ8 on BSM, irrespective of

the used IVD12 ascites dilution. 3

Diabetes Page 48 of 49

SUPPLEMENTAL FIGURE 4

2 5 0 0 0 0 1 0 0 0 0 0 0

2 0 0 0 0 0 8 0 0 0 0 0

1 5 0 0 0 0 6 0 0 0 0 0

1 0 0 0 0 0 4 0 0 0 0 0 Counts (CPM) Counts (CPM) 5 0 0 0 0 2 0 0 0 0 0

0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300  M  M ZAAISAAELRHVAA ZAAFQGARIITGAA Kd 6.171 Kd 240

3 0 0 0 0 0 2 0 0 0 0 0

1 5 0 0 0 0 2 0 0 0 0 0 1 0 0 0 0 0

1 0 0 0 0 0 Counts (CPM) Counts (CPM) 5 0 0 0 0

0 0 0 2 5 5 0 7 5 1 0 0 0 50 100 150 200 250 300  M  M ZAALETMTILRAAA ZAAVKGSSLHVGAA Kd 2.009 Kd 0.8445

2 0 0 0 0 0 4 0 0 0 0 0

1 5 0 0 0 0 3 0 0 0 0 0

1 0 0 0 0 0 2 0 0 0 0 0 Counts (CPM) Counts (CPM) 5 0 0 0 0 1 0 0 0 0 0

0 0 0 2 5 5 0 7 5 1 0 0 0 2 5 5 0 7 5 1 0 0  M  M ZAAIGTSSVARAAA ZAAVAYSKAATVAA Kd 1.028 Kd 4.76

1 0 0 0 0 0 0 2 5 0 0 0 0 8 0 0 0 0 0 2 0 0 0 0 0

6 0 0 0 0 0 1 5 0 0 0 0

4 0 0 0 0 0 1 0 0 0 0 0 Counts (CPM) Counts (CPM)

2 0 0 0 0 0 5 0 0 0 0

0 0 0 2 5 5 0 7 5 1 0 0 0 50 100 150 200 250 300  M  M ZAALGAVKNVWQAA ZAAAPKGSVLQEAA Kd 10.97 Kd 1.988

To obtain an indicator peptide for the peptide-binding studies with HLA-DQ6, eluted peptides from HLA-DQ6/6 homozygous EBV-BLCL were tested in direct peptide-binding assays. For this, predicted core-nonamers of DQ6-eluted peptides were extended with two alanine residues both at the N- and C-terminus and a biotin label was added at the N-terminus. Peptide sequences of the tested biotinylated peptides are shown. Data are obtained from two independent experiments each in duplicate. Curves are fitted according to a one-site binding hyperbola using GraphPad Prism. Data represent ± SEM. 4

Page 49 of 49 Diabetes

SUPPLEMENTAL FIGURE 5

1 PPI

M) 

0 ( .1

5 0

1 /IC

 0 .0 1

1 IA -2

M)

 0 ( .1 5 0

1 /IC

 0 .0 1 D Q 6 D Q 8

Natural processed and DQ6-presented peptides eluted from DQ6/8 expressing DC were tested

for binding DQ6.2 and DQ8. The following peptides were confirmed: in the upper panel PPI14-

22 and in the lower panel IA-2374-386, IA-2498-511, IA-2543-566 and IA-2582-59 (from left to right)

eluted from the four distinct core regions of IA-2. EC50 values were calculated on the basis of competition between the biotinylated indicator peptide and the test peptides. Data represent

mean ± SEM (n=3). Shown on the x-axes is 1/EC50, illustrating that larger bars represent better binding.

5