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Reproducible Association with Type 1 Diabetes in the Extended Class I Region of the Major Histocompatibility Complex

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Reproducible Association with Type 1 Diabetes in the Extended Class I Region of the Major Histocompatibility Complex Genes and Immunity (2009) 10, 323–333 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex MK Viken1,2,10, A Blomhoff3,10, M Olsson4,5, HE Akselsen6, F Pociot7, J Nerup7, I Kockum8, A Cambon-Thomsen9, E Thorsby1,2, DE Undlien3,6 and BA Lie2 1Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway; 2Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway; 3Institute of Medical Genetics, Faculty Division Ulleva˚l University Hospital, University of Oslo, Oslo, Norway; 4Department of Mathematical Statistics, Chalmers University of Technology, Go¨teborg, Sweden; 5Department of Mathematical Statistics, Go¨teborg University, Go¨teborg, Sweden; 6Department of Medical Genetics, Ulleva˚l University Hospital, Oslo, Norway; 7Steno Diabetes Centre, Gentofte, Denmark; 8Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden and 9Inserm U 558, University Paul Sabatier, Toulouse, France The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401- DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D. Genes and Immunity (2009) 10, 323–333; doi:10.1038/gene.2009.13; published online 19 March 2009 Keywords: association; type 1 diabetes; HLA; xMHC; BTN; PRSS16 Introduction MHC-linked T1D susceptibility genes, as they observed that siblings of DR3/DR4-DQ8 T1D patients, who were Type 1 diabetes (T1D) is a multifactorial disease, caused identical by descent for both extended HLA haplotypes, by an interaction of both genetic and environmental had a considerably higher risk than the DR3/DR4-DQ8 factors. Years of research, as well as a recent large siblings not sharing both of these extended haplotypes. genome-wide association study agree that the major We have earlier performed a microsatellite screen of genetic contribution to T1D resides within the extended the xMHC and found an association with D6S2223 in the major histocompatibility complex (xMHC),1 in which extended class I region, independent of linkage disequi- the human leukocyte antigen (HLA) class II genes, and librium (LD) with the known HLA class II risk alleles.4,6 particularly the DRB1*03-DQA1*0501-DQB1*0201 and The association was observed as a reduced transmis- the DRB1*04-DQA1*03-DQB1*0302 haplotypes confer sion of allele D6S2223*3 from DRB1*03-DQA1*0501- the highest risk.2 However, accumulating evidence DQB1*0201 homozygous parents in a combined T1D shows that these class II genes cannot explain the entire dataset from Norway, Sweden, Denmark, United King- T1D association with the xMHC.3–7 Recently, Aly et al.8 dom and France (11T vs 46NT, P ¼ 0.000004).4,6 Interest- provided further evidence for the existence of additional ingly, others have suggested that if additional T1D risk factors exist on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, these are situated centromeric of HLA-DRB1 Correspondence: Dr BA Lie, Institute of Immunology, Rikshospita- and telomeric of HLA-A.9 let University Hospital, Sognsvannsveien 20, Oslo 0027, Norway. The xMHC is characterized by strong and extended E-mail: [email protected] 10,11 10These authors contributed equally to work. LD, making it difficult to pinpoint the causal 12 Received 23 December 2008; revised and accepted 13 February 2009; variant(s). The LD pattern is also intricate and vary published online 19 March 2009 with regard to the underlying ancestral HLA haplo- Reproducible association with T1D in the xMHC MK Viken et al 324 types.13,14 Thus, attention must be paid to the HLA associated D6S2223 marker and 43 microsatellites span- haplotype distributions in the population being studied. ning the xMHC used in our earlier LD screen.15 A 0 Of relevance for T1D, the LD on the DRB1*03- significant D 40.3 (Pnco0.05) was used as a cut-off DQA1*0501-DQB1*0201 haplotype is generally stretching criterion, as this has been estimated to be the minimal over longer distances than on the DRB1*0401-DQA1*03- usable amount of LD in association studies,22 resulting in DQB1*0302 haplotype, making it harder to capture an a region of B0.8 Mb (between D6S306 and D6S1558). association on the latter haplotype.15 This could explain Single-point associations were obtained by the homo- why the association with D6S2223 was only observed on zygous parent transmission disequilibrium test sepa- the DRB1*03-DQA1*0501-DQB1*0201 haplotype. Further- rately from DRB1*03-DQA1*0501-DQB1*0201 and more, for fine-mapping purposes the DRB1*0401- DRB1*0401-DQA1*03-DQB1*0302 homozygous parents DQA1*03-DQB1*0302 haplotype, with less extensive for the 50 SNPs successfully genotyped in the initial LD, might prove to be especially useful. Finally, these dataset of 205 families (Figure 1). The associated SNPs differential LD patterns make it imperative to map the from this first phase screen were located telomeric of T1D association separately on these HLA haplotypes. D6S2223, except rs9295746. As the associated SNPs on The extended class I region harbors several T1D the DRB1*0401-DQA1*03-DQB1*0302 haplotype were candidate genes involved in immunological processes,16 localized at the very telomeric end of the initially defined including the PRSS16 gene, a cluster of seven butyr- 0.8 Mb region (Figure 1), the SNP screen was extended ophilin (BTN) genes that are members of the immuno- telomerically to cover B1.9 Mb (second phase screen). globulin superfamily,17 and zinc-finger protein genes When analyzing the 134 SNPs from the first and encoding transcriptional regulators involved in cell second phase screen together in the initial dataset, only growth and differentiation.18 The PRSS16 gene is eight showed association (Po0.05) on the DRB1*0401- predominantly expressed in the cortical epithelial cells DQA1*03-DQB1*0302 haplotypic background (Table 1 of the thymus, and has been suggested to play a role in and Figure 1, triangles). Seven of these associated SNPs the positive selection of T cells or in T-cell regulation.19 covered an 85-kb region, in which PRSS16 is the only We have earlier screened this candidate gene for novel known protein-coding gene, and all showed the same polymorphisms,20 but none of the polymorphisms within transmission distortion (13%T (95%CI, 10–35%), P ¼ 0.02) the PRSS16 gene could explain the association observed and were in perfect LD on this haplotypic background. with D6S2223 on the DRB1*03-DQA1*0501-DQB1*0201 The last associated SNP (rs12201890; 0T vs 5NT, haplotypic background.21 P ¼ 0.008) was situated B482 kb telomeric of, and in In the current study, we performed a single nucleotide strong LD with, these seven SNPs (r2 ¼ 0.91). The seven polymorphism (SNP) screen to further limit the asso- SNPs showed a D0 ¼ 0.66 and r2 ¼ 0.11 with D6S2223*3, ciated region defined by the microsatellites analyzed whereas rs12201890 showed D0 ¼ 0.51 and r2 ¼ 0.07. earlier.4,6,15 Initially, we analyzed the transmission of Three additional SNPs were selected as candidate SNPs; SNPs in 205 families with DRB1*03-DQA1*0501- that is, rs9379857 and rs1985732 were selected on the DQB1*0201 and DRB1*0401-DQA1*03-DQB1*0302 homo- basis of reported association with allelic gene expression zygous parents, and paid particular attention to the differences of the BTN3A2 gene,23 and rs996247 (B22 kb association on the DRB1*0401-DQA1*03-DQB1*0302 hap- upstream of PRSS16) was included on the basis of a lotype, as the less extensive LD on this haplotype could reported novel association with T1D.24 None of these guide us closer to the causal variant. Thereafter, candidate SNPs showed association on the DRB1*0401- identified associations were replicated in 725 families DQA1*03-DQB1*0302 haplotype (Figure 1). from the Type 1 Diabetes Genetics Consortium (T1DGC), Twelve polymorphisms from the first and second and were also checked against other associations genotyping phases (11 SNPs and a 15-bp insertion/ observed in the MHC, like the HLA class I loci. deletion) showed association with T1D on the DRB1*03- DQA1*0501-DQB1*0201 haplotype (Table 1), all of which were scattered throughout the region (Figure 1, circles). It is interesting to note that one of the three candidate Results SNPs, rs9379857, presumably influencing the expression Our available dataset has changed over time (mainly of BTN3A2 was associated on the DRB1*03-DQA1*0501- because of the lack of DNA), therefore we reanalyzed DQB1*0201 haplotype (Table 1).
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