SUPPLEMENTARY DATA Principal Investigators and Acknowledgment

Hispanic Community Health Study/Study of Latinos (HSHC/SOL) Robert Kaplan, Sylvia Wassertheil-Smoller (Bronx); Martha L. Daviglus, Aida L. Giachello (Chicago); Neil Schneiderman, David Lee, Leopoldo Raij, John Ryan (Miami); Greg Talavera, John Elder, Matthew Allison, Michael Criqui (San Deigo).

The authors thank the staff and participants of HCHS/SOL for their important contributions. A complete list of staff and investigators has been provided by Sorlie P., et al. in Ann Epidemiol. 2010 ;20:642-649 and is also available on the study website http://www.cscc.unc.edu/hchs/. The baseline examination of the Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contributed to the HCHS/SOL first funding period through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the NIH Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Genotyping efforts were supported by NHLBI HSN 26220/20054C, NCATS CTSI grant UL1TR000123, and NIDDK Diabetes Research Center (DRC) grant DK063491.

Starr County Health Study (SCHS) We thank the field staff in Starr County for their collection of these data and are grateful to the study participants who gave of their time and contributed to this study. This work was supported in part by grants DK073541, DK020595, AI085014, DK085501, and HL102830 from the National Institutes of Health and funds from the University of Texas Health Science Center at Houston. These studies (protocol SPH-02-042) were approved by the University of Texas Health Science Center at Houston’s Committee for the Protection of Human Subjects and carried out in a manner consistent with the Declaration of Helsinki. The studies were explained to all participants and written informed consent obtained. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268200782096C.

Boston Puerto Rican Health Study (BPRHS) Katherine Tucker. The Boston Puerto Rican Health Study was funded by National Heart, Lung, and Blood Institute grant P50-HL105185 and National Institute on Aging grant P01-AG023394.

BioMe Biobank Judy H Cho. We thank the participants in the BioMe Biobank for their invaluable contribution to biomedical research. Funding for the BioMe Biobank program is supported by the Andrea and Charles Bronfman Philanthropies.

HCHS/SOL SCHS BPRHS BioMe-OMNIBioMe-MEGA No. of participants, n All 9636 395 832 1867 1683 men 4040 89 245 640 564 women 5596 306 587 1227 1119 Age, years 43.8 (13.8) 48.13 (8.68) 56.0 (NA) 50.2 (14.7) 51.3 (14.8) HbA1c, % 5.47 (0.36) 5.45 (0.35) 6.09 (NA) 5.55 (0.41) 5.56 (0.42) Hispanic background, n Central American 1097 0 0 76 50 Cuban 1750 0 0 25 17 Dominican 904 0 0 244 278 Mexican 3558 395 0 35 42 Puerto Rican 1533 0 831 488 404 South American 765 0 0 152 204

Data are mean (SD) or sample size (n).

Allele HCHS/SOL Replication studies* Combined P SNP Nearest locus Chr Position Effect Other EAF Beta (SE) P Beta (SE) P (SOL+ replication)† rs113282222b CEP104 1 3718591 TGGAG T 0.173 -0.031 (0.006) 9.98E-07 -0.006 (0.012) 0.595 5.94E-06 rs199584848b TM1EM206 1 212544641 A AAG 0.024 0.080 (0.015) 1.74E-07 0.006 (0.102) 0.953 2.27E-07 rs113119484a CADM2 3 85463419 T G 0.013 -0.102 (0.021) 8.86E-07 0.016 (0.034) 0.642 7.42E-05 rs10513537b IQCJ−SCHIP1 3 158904859 G A 0.209 0.031 (0.006) 3.83E-07 0.003 (0.012) 0.778 3.07E-06 rs74638476b ETV5 3 185735512 T C 0.026 0.079 (0.016) 8.03E-07 -0.005 (0.029) 0.872 2.32E-05 rs73774950a NUDT12 5 102957617 C T 0.024 -0.089 (0.016) 3.09E-08 0.016 (0.024) 0.513 2.19E-05 rs11752643a HLA−DQA2 6 32669373 T C 0.017 0.096 (0.018) 1.76E-07 0.012 (0.035) 0.737 1.77E-06 rs6949071b ETV1 7 13655049 C G 0.459 -0.025 (0.005) 4.50E-07 0.005 (0.010) 0.646 1.70E-05 rs6992753b UNC5D 8 35926402 A G 0.016 0.111 (0.020) 3.48E-08 0.017 (0.030) 0.581 9.51E-07 rs116781682b FAM188A 10 16218532 T C 0.012 -0.118 (0.023) 2.11E-07 -0.050 (0.035) 0.156 2.82E-07 rs334b HBB 11 5248232 A T 0.013 -0.305 (0.023) 2.72E-40 -0.127 (0.044) 0.004 2.94E-39 rs73393695a FBXO21 12 117644934 A G 0.051 -0.056 (0.011) 6.38E-07 -0.001 (0.020) 0.975 1.21E-05 rs145546625b HBM 16 220583 T C 0.066 0.059 (0.010) 8.20E-09 0.044 (0.023) 0.050 1.42E-09 rs144212976b RAB11FIP4 17 29821839 G A 0.020 0.087 (0.017) 5.51E-07 -0.013 (0.037) 0.719 1.24E-05 rs2748424b TMC6 17 76124865 G C 0.179 0.051 (0.006) 1.98E-15 0.032 (0.012) 0.008 1.49E-16 rs74575505b SIGLEC12 19 51942103 G A 0.128 0.036 (0.007) 7.27E-07 -0.007 (0.014) 0.622 2.67E-05 rs56222990b PDGFB 22 39652947 G C 0.069 0.045 (0.010) 6.34E-06 0.012 (0.017) 0.482 1.36E-04 rs1050828a G6PD X 153764217 T C 0.020 -0.346 (0.014) 9.59E-132 -0.292 (0.099) 0.003 1.34E-133

Chr, chromosome; Position: GRCh37 reference; EAF: effect allele frequency; Beta: effect size (%) for each effect allele of SNP on HbA1c. *Results from 4 replication studies (see Supplemental Table 3) were combined by fixed effect meta-analysis. †Results from SOL and replication studies were combined using by fixed effect meta-analysis. a genotyped in HCHS/SOL b imputed in HCHS/SOL. All imputation quality in HCHS/SOL >0.9 SNPs in bold had P≤0.05 in combined replication studies

Allele SCHS BPRHS BioMe-OMNI BioMe-MEGA SNP Gene Chr Position Effect Other EAF β (SE) P EAF β (SE) P EAF β (SE) P EAF β (SE) P

rs113282222 CEP104 1 3718591 TGGAG T 0.161 -0.041 (0.033) 0.218 0.202 0.016 (0.058) 0.785 0.188 0.037 (0.017) 0.031 0.194 -0.047 (0.018) 0.011

rs199584848 TMEM206 1 212544641 A AAG 0.012 0.179 (0.127) 0.159 0.020 -0.305 (0.171) 0.074 NA NA NA NA NA NA

rs113119484 CADM2 3 85463419 T G 0.019 -0.057 (0.091) 0.533 0.016 0.168 (0.175) 0.336 0.017 0.011 (0.051) 0.829 0.017 0.034 (0.056) 0.546

rs10513537 IQCJ−SCHIP1 3 158904859 G A 0.267 -0.017 (0.026) 0.522 0.155 0.043 (0.056) 0.445 0.157 0.006 (0.018) 0.725 0.143 0.007 (0.022) 0.739

rs74638476 ETV5 3 185735512 T C 0.003 -0.043 (0.233) 0.854 0.031 -0.011 (0.164) 0.948 0.029 0.003 (0.042) 0.953 0.032 -0.010 (0.041) 0.812

rs73774950 NUDT12 5 102957617 C T 0.003 -0.095 (0.240) 0.691 0.030 0.176 (0.113) 0.119 0.045 -0.014 (0.032) 0.667 0.036 0.043 (0.039) 0.269

rs11752643 HLA−DQA2 6 32669373 T C 0.015 0.066 (0.138) 0.630 NA NA NA 0.021 -0.022 (0.047) 0.645 0.017 0.049 (0.056) 0.377

rs6949071 ETV1 7 13655049 C G 0.420 0.027 (0.026) 0.288 0.489 0.057 (0.038) 0.138 0.492 -0.017 (0.015) 0.275 0.495 0.010 (0.016) 0.538

rs6992753 UNC5D 8 35926402 A G 0.005 0.023 (0.175) 0.897 0.027 0.018 (0.172) 0.915 0.027 -0.011 (0.041) 0.780 0.025 0.056 (0.049) 0.249

rs116781682 FAM188A 10 16218532 T C NA NA NA 0.021 -0.559 (0.165) 0.001 0.019 -0.056 (0.051) 0.274 0.020 0.006 (0.052) 0.915

rs334 HBB 11 5248232 A T 0.005 0.005 (0.182) 0.978 0.020 -1.190 (0.168) 0.000 0.011 0.039 (0.067) 0.562 0.013 -0.138 (0.064) 0.032

rs73393695 FBXO21 12 117644934 A G 0.028 -0.049 (0.092) 0.591 0.076 -0.101 (0.069) 0.144 0.066 -0.022 (0.029) 0.445 0.058 0.057 (0.033) 0.085

rs145546625 HBM 16 220583 T C 0.073 0.079 (0.046) 0.086 0.020 -0.062 (0.208) 0.766 0.027 0.023 (0.041) 0.568 0.041 0.043 (0.035) 0.225

rs144212976 RAB11FIP4 17 29821839 G A 0.032 0.021 (0.069) 0.758 0.011 -0.094 (0.218) 0.666 0.012 -0.049 (0.063) 0.438 0.014 0.000 (0.062) 0.995

rs2748424 TMC6 17 76124865 G C 0.195 0.072 (0.035) 0.038 NA NA NA 0.228 0.026 (0.017) 0.128 0.250 0.027 (0.019) 0.154

rs74575505 SIGLEC12 19 51942103 G A 0.109 -0.012 (0.038) 0.762 0.116 -0.062 (0.060) 0.302 0.115 -0.021 (0.022) 0.320 0.111 0.021 (0.024) 0.380

rs56222990 PDGFB 22 39652947 G C 0.039 0.092 (0.078) 0.234 0.106 0.051 (0.065) 0.437 0.084 0.051 (0.026) 0.051 0.093 -0.041 (0.026) 0.113

rs1050828 G6PD X 153764217 T C NA NA NA 0.026 -0.292 (0.098) 0.003 NA NA NA NA NA NA

A1: effect allele; A2: reference allele; EAF: effect allele frequency; Beta: Effect size (%) for each effect allele of SNP on HbA1c.

Hispanic/Latino HBB rs334 HBM rs145546625 TMC6 rs2748424 G6PD rs1050828 background EAF Beta P EAF Beta P EAF Beta P EAF Beta P Central American 0.018 0.298 (0.058) 2.8E-07 0.108 -0.040 (0.023) 8.6E-02 0.147 -0.059 (0.020) 3.9E-03 0.012 0.325 (0.050) 1.2E-10 Cuban 0.016 0.259 (0.053) 1.0E-06 0.015 -0.053 (0.052) 3.1E-01 0.189 -0.062 (0.015) 6.3E-05 0.027 0.367 (0.031) 9.4E-33 Dominican 0.039 0.311 (0.047) 3.1E-11 0.014 -0.095 (0.081) 2.4E-01 0.265 -0.058 (0.020) 3.3E-03 0.068 0.367 (0.026) 1.1E-46 Mexican 0.004 0.387 (0.072) 8.3E-08 0.105 -0.075 (0.012) 2.6E-09 0.157 -0.051 (0.010) 9.0E-07 0.004 0.352 (0.050) 1.5E-12 Puerto Rican 0.016 0.327 (0.056) 6.7E-09 0.012 -0.020 (0.063) 7.5E-01 0.218 -0.042 (0.016) 1.0E-02 0.031 0.327 (0.030) 2.0E-27 South American 0.006 0.318 (0.104) 2.3E-03 0.11 -0.024 (0.024) 3.1E-01 0.125 -0.018 (0.022) 4.3E-01 0.007 0.124 (0.086) 1.5E-01 P for heterogeneity 0.82 0.41 0.66 0.14

EAF: effect allele frequency; Beta: Effect size (%) for each effect allele of SNP on HbA1c.

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA Supplementary Table S5. Associations between novel SNPs and HbA1c on 7833 subjects without iron deficiency or anemia. Iron deficiency is defined by low serum iron levels (<60 mcg/dL), elevated total iron binding capacity (>450 mcg/dL), or low serum ferritin (<12 ng/mL). Anemia is defined by low hemoglobin levels (<11 g/dL for female, <12 g/dL for non-pregnant women, and <13 g/dL for men).

Beta, SNP Gene Chr Position Effect Other SE, % P-value % rs334 HBB 11 5248232 A T -0.33 0.03 1.6E-35 rs145546625 HBM 16 220583 T C 0.06 0.01 8.4E-08 rs2748424 TMC6 17 76124865 G C 0.05 0.01 1.4E-12 rs1050828 G6PD X 153764217 T C -0.35 0.02 1.1E-116

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA Supplementary Table S6. Marginal and conditional associations of our lead SNP and previously reported SNPs in TMC6 gene region with HbA1c in the HCHS/SOL

Allele HCHS/SOL r2 with rs2748424 from 1000 Genome* Discovered in: SNP Chr Position East South Function of SNP Ethnicity Effect Other EAF r2 P-value Conditional P Hispanics European African Asian Asian HCHS/SOL: 2.8×10-5 a rs2748424 US 17 76124865 G C 0.179 1.00 2.0×10-15 3.1×10-5 b 1.00 1.00 1.00 1.00 1.00 Upstream of TMC6 Hispanics/Latinos 1.1×10-11 c Exonic region of Hachiya et al. TMC6. Missense rs2748427 (2017): 17 76121864 A G 0.233 0.70 1.5×10-12 5.9×10-1 † 0.77 0.82 0.35 0.67 0.53 mutation Trp -> Japanese Arg. Prins et al. (2017): Intronic region of rs761772 17 76122078 T C 0.121 0.53 5.1×10-13 7.8×10-1 † 0.58 0.57 0.18 0.65 0.72 European TMC6 Wheeler et al. Intronic region of rs2073285 (2017): 17 76117361 T C 0.277 0.10 2.7×10-9 6.2×10-5 † 0.07 0.05 0.02 0.14 0.03 TMC6 Trans-ethnic

* LD calculated from Phase 3 of the 1000 Genomes Project a. Conditional on rs2748427 b. Conditional on rs761772 c. Conditional on rs2073285 † Conditional on rs2748424

SNP rs334 rs145546625 rs2748424 rs1050828 Gene HBB HBM TMC6 G6PD Chromosome 11 16 17 23 Position 5248232 220583 76124865 153764217 Effect/other Allele A/T T/C G/C T/C Blood traits n 12502 12502 12502 12489 Red Blood Cell Count Beta 0.040 0.029 0.019 -0.131 P 8.26e-02 4.83e-03 2.17e-03 1.41e-19 n 12502 12502 12502 12489 Hemoglobin Beta -0.164 -0.099 0.019 -0.128 P 2.50e-02 2.15e-03 3.30e-01 5.99e-03 n 12502 12502 12502 12489 Hematocrit Beta -1.316 -0.282 0.078 -0.264 P 1.31e-10 1.71e-03 1.66e-01 4.36e-02 n 12502 12502 12502 12489 MCV Beta -3.459 -1.129 -0.179 1.900 P 1.05e-22 3.66e-13 6.43e-02 2.34e-17 n 12502 12502 12502 12489 MCH Beta -0.570 -0.393 -0.072 0.546 P 1.34e-05 9.30e-12 4.52e-02 4.85e-11 n 12500 12500 12500 12487 MCHC Beta 0.665 -0.023 -0.014 -0.086 P 3.61e-16 5.17e-01 5.27e-01 1.01e-01 n 12501 12501 12501 12488 RDW Beta 0.017 0.004 0.004 -0.037 P 9.62e-04 7.23e-02 1.28e-02 3.70e-29 n 12491 12491 12491 12478 Platelet Count Beta -0.250 0.144 -0.036 -0.028 P 3.76e-02 6.59e-03 2.80e-01 7.13e-01 Iron traits n 12530 12530 12530 12517 Serum Iron Beta -0.12 -0.09 -0.06 0.29 P 2.7E-01 7.0E-02 3.4E-02 3.0E-05 n 12297 12297 12297 12284 Ferritin Beta -0.02 -0.01 0.00 0.04 P 2.9E-01 3.1E-01 9.7E-01 2.0E-03 n 12536 12536 12536 12523 Total Iron Binding Capacity Beta 0.01 -0.02 -0.02 -0.12 P 9.2E-01 5.2E-01 2.7E-01 1.3E-02 n 12539 12539 12539 12526 % Transferrin Saturation Beta -0.08 -0.04 -0.02 0.20 P 2.2E-01 1.6E-01 1.6E-01 1.1E-06 Glycemic traits n 10065 10065 10065 10054 Fasting glucose Beta 0.350 0.011 0.359 -0.168 P 5.08e-01 9.62e-01 1.40e-02 6.14e-01 n 10053 10053 10053 10042 Fasting insulin Beta 0.038 -0.003 0.007 -0.011 P 2.03e-02 6.47e-01 1.28e-01 2.76e-01 n 9622 9622 9622 9613 2-h glucose Beta 3.095 1.422 -0.030 -0.698 P 1.18e-01 1.08e-01 9.56e-01 5.85e-01 n 10052 10052 10052 10041 HOMA-IR Beta 0.040 -0.003 0.009 -0.012 P 2.17e-02 6.74e-01 7.32e-02 2.70e-01 n 10045 10045 10045 10034 HOMA-B Beta 0.034 -0.005 0.002 -0.009 P 3.97e-02 4.60e-01 7.15e-01 3.89e-01 Liver traits n 10708 10708 10708 10708 AST/Platelet Ratio Beta -0.003 -0.015 0.004 -0.011 P 8.06e-01 5.67e-03 2.20e-01 2.00e-01 n 10778 10778 10778 10778 Suspected NAFLD Beta -0.058 -0.064 0.027 -0.426 P 7.59e-01 3.83e-01 5.72e-01 9.94e-03

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA n 10793 10793 10793 10793 AST Beta -0.020 -0.007 0.003 -0.011 P 3.57e-02 1.11e-01 2.54e-01 8.65e-02 n 10780 10780 10780 10780 ALT Beta -0.013 -0.007 0.003 -0.015 P 3.30e-01 2.82e-01 3.82e-01 1.06e-01

Beta: Effect size for each effect allele of SNP on traits. MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW, red blood cell distribution width; HOMA-IR, homeostatic model assessment of insulin resistance; HOMA-B, homeostatic model assessment of β-cell function; AST, aspartate aminotransferase; NAFLD, nonalcoholic fatty liver disease; ALT, alanine aminotransferase. P-values in bold passed the significant level (P<5.95e-04) after multiple testing correction (4 SNPs × 21 traits).

All Men Women Among without diagnosed diabetes N Mean HbA1c, % N Mean HbA1c, % N Mean HbA1c, % HBB-rs334 TT 2 5.22 (0.07) 1 5.10 (NA) 1 5.30 (NA) TA 222 5.22 (0.05) 90 5.23 (0.08) 132 5.22 (0.06) AA 10246 5.50 (0.01) 4287 5.50 (0.01) 5959 5.49 (0.01) Beta (SE) per T-allele, %* -0.33 (0.05) -0.32 (0.08) -0.34 (0.05) G6PD-rs1050828 AA/AO 91 4.83 (0.09) 80 4.84(0.10) 11 4.74(0.11) AG 218 5.20(0.05) 0 NA 218 5.20(0.05) GG 10150 5.50(0.01) 4289 5.50 (0.01) 5861 5.50(0.01) Beta (SE) per A-allele, %* -0.35 (0.03) -0.38 (0.04) -0.31 (0.04)

Data are mean (SE) accounting for complex study design of HCHS/SOL. * Effects are estimated with adjustment of age, center, 5 PCs for ancestry, among subjects without diagnosed diabetes and blood disorders (self-reported or sickle cell disease by homozygous of HBB-rs334 T allele)

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA Supplementary Table S9. Characteristics of carriers and non-carriers of HBB-rs334 or G6PD- rs1050828 minor alleles without diagnosed diabetes in the HCHS/SOL

Carriers Non-carrier P-value N 515 (4.9%) 9942 (95.1%) Age, years 40.2 (0.9) 39.8 (0.3) 0.67 Sex <0.004 Male 165 (4.1%) 4203 (95.9%) Female 350 (5.9%) 5739 (94.1%) Hispanic/Latino background <0.001 Dominican 157 (17.7%) 807 (82.3%) Central American 57 (4.8%) 1121 (95.2%) Cuban 115 (5.5%) 1786 (94.5%) Mexican 37 (0.9%) 3782 (99.1%) Puerto Rican 118 (6.3%) 1551 (93.7%) South American 21 (2.6%) 785 (97.4%) Fasting glucose, mg/dL 94.7 (0.9) 96.0 (0.3) 0.14 2h glucose, mg/dL 116.1 (2.5) 117.7 (0.7) 0.50 HbA1c, % 5.1 (0.04) 5.5 (0.01) <0.001

Data are mean (SE) for continuous variables and N (%) for categorical variables, accounting for complex study design of HCHS/SOL.

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA Supplementary Table S10. Prevalence of diabetes estimated based on fasting glucose, 2-hour glucose and HbA1c in carriers and non-carriers of HBB-rs334 or G6PD-rs1050828 minor alleles without diagnosed diabetes

Carrier Non-carrier P-value Prevalence of diabetes (95% CI) Fasting glucose ≥126 mg/dL 2.1% 2.0% 0.88 (0.9-3.4%) (1.7-2.4%) Post-OGTT glucose ≥200 mg/dL 3.1% 4.5% 0.15 (1.5-4.7%) (4.0-5.1%) Measured HbA1c ≥6.5% (48mmol/mol) 1.8% 2.9% 0.15 (0.6-2.9%) (2.4-3.3%) Fasting glucose ≥126 mg/dL, post-OGTT 4.3% 6.1% 0.10 glucose ≥200 mg/dL, or HbA1c ≥6.5% (2.6-6.1%) (5.5-6.7%) Genetically adjusted HbA1c ≥6.5% 4.0% 2.9% 0.13 (2.3-5.7%) (2.4-3.3%) Fasting glucose≥126 mg/dL, post-OGTT glucose ≥200 mg/dL, or 5.3% 6.1% 0.48 genetically adjusted HbA1c (3.3-7.3%) (5.5-6.7%) ≥6.5%(48mmol/mol)

Data are prevalence, accounting for complex study design of HCHS/SOL.

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA Supplementary Table S11. Comparison of HbA1c levels and prevalence of prediabetes estimated based on fasting glucose, 2-hour glucose and HbA1c in low and medium-to-high unweighted erythrocyte genetic risk score (GRS) of 5 erythrocyte-associated genetic variants (ANK1-rs4737010, HK1- rs72805692, TMPRSS6-rs855791, HBM-rs145546625, TMC6-rs2748424), excluding diagnosed diabetes.

Medium‐High Low erythrocyte GRS (≤2) erythrocyte GRS (2< P‐value GRS)

# of subjects (%) 917 (8.7) 9550 (91.2)

# of subjects with G6PD and rs334 carrier (%) 46 (5) 469 (4.9) 0.98*

HbA1c level, % (95% CI) 5.38 (5.34‐5.42) 5.5 (5.48‐5.52) 1.2×10‐7

Prevalence of hyperglycemia, % (95% CI)

Fasting glucose ≥100 mg/dL 25.28 (21.51‐29.04) 25.42 (23.98‐26.86) 0.94

Post‐OGTT glucose ≥140 mg/dL 21.12 (17.4‐24.83) 21.74 (20.38‐23.1) 0.75

Measured HbA1c ≥5.7% (39 mmol/mol) 21.89 (18.45‐25.33) 28.13 (26.85‐29.42) 0.001

Fasting glucose ≥100 mg/dL, post‐OGTT 43.61 (39.4‐47.83) 46.07 (44.43‐47.72) 0.27 glucose ≥140 mg/dL, or HbA1c ≥5.7% (39 mmol/mol)

Data are account for complex study design of HCHS/SOL * P-value from Fisher’s exact test

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA Supplementary Figure S2. (a) Regional plot of associations with HbA1c around TMC6 region (lead SNP rs2748424) in the HCHS/SOL. (b) Regional plot of associations with HbA1c conditional on lead SNP (rs2748424) around TMC6 region in the HCHS/SOL. SNPs in purple text are previously reported SNPs.

©2019 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0168/-/DC1 SUPPLEMENTARY DATA Supplementary Figure S3. Overall scatterplots of measured HbA1c and genetically adjusted HbA1c vs. fasting glucose in carriers and non- carriers of HBB-rs334 or G6PD rs1050828 minor alleles without diagnosed diabetes