Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major Histocompatibility Complex

Abstract

(DR3/4-DQ8) siblings who share both major histocompatibility complex (MHC) haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-bydescent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes. RESEARCH DESIGN AND METHODS-We completed an extensive single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium.RESULTS-We found evidence for an association with type 1A diabetes (rs1233478, P ϭ 1.6 ϫ 10 Ϫ23 , allelic odds ratio 2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the "8.1 haplotype." The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, P ϭ 1.4 ϫ 10 Ϫ12 ) and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B, and HLA-A (P ϭ 0.01). CONCLUSIONS-Polymorphisms

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

“…Both single SNPs and five-SNP haplotypes showed association in this region, and we also replicated the association observed here. Recently Aly et al 24 reported an association with T1D upstream of PRSS16, but this SNP (rs996247) showed no association in our dataset. However, overall there is a strong evidence for an association around the PRSS16 gene.…”

“…Furthermore, in the earlier T1DGC screen we have also reported association with SNPs near HLA-G, that is, rs4122198, rs1619379 and rs2394186, 25 and others have reported association with SNPs in the UBD/MAS1L region (particularly with rs1233478). 24 When conditioning on each of these SNPs (together with DRB1-DQA1-DQB1 and HLA-B), the association with the SNPs in the extended class I region remained significant and vise versa, except for the PRSS16 SNP rs9393796 when adjusting for rs2394186 (data not shown). Both these SNPs seemed to reduce each other's effect, thereby indicating some sort of dependency between these associations.…”

“…Three additional SNPs were selected as candidate SNPs; that is, rs9379857 and rs1985732 were selected on the basis of reported association with allelic gene expression differences of the BTN3A2 gene, 23 and rs996247 (B22 kb upstream of PRSS16) was included on the basis of a reported novel association with T1D. 24 None of these candidate SNPs showed association on the DRB1*0401-DQA1*03-DQB1*0302 haplotype (Figure 1). …”

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…A DRB1-DQA1-DQB1-independent association between T1D and certain HLA-B alleles has been demonstrated in several reports, [3][4][5][6]10,18 but most convincingly by a British combined case-control/family study 3 and in a large family material provided by the T1DGC. 18 In both earlier studies and this study, the most consistent evidence was observed for the B*39 and B*18 alleles, with demonstrated independence of a high number of neighboring markers.…”

“…1,2 However, numerous studies have strongly implicated additional T1D risk loci within the MHC. [3][4][5][6][7][8][9][10][11][12] This complex contains an unusually high density of genes involved in immunological responses, 13 of which many are good candidates for involvement in autoimmune processes. The observation of multiple susceptibility loci in the MHC is shared with a number of other AIDs, including ankylosing spondylitis, celiac disease, Graves' disease, juvenile idiopathic arthritis, multiple sclerosis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus and ulcerative colitis (cf.…”