Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Abstract

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.

Figure 1. Association analyses across the MHC

a, b, -log₁₀(P) versus chromosome position. Unconditional single locus analyses are presented for loci typed in up to 850 families (a) and in up to 2,049 cases and 1,125 controls (b, first case–control set). c, d, Analyses conditional on HLA-DRB1 and HLA-DQB1 in the families (c) and in the first case–control set (d). Results are listed in Supplementary Tables 1 and 2.

Figure 2. Association analyses of 1,475 SNPs across the MHC

a, Unconditional single locus analysis in up to 1,964 cases and 2,923 controls—the limits of the association are at 25.9 Mb (rs1324088 P=4.65×10^-6) and 34.0 Mb (rs6941621 P=9.95×10^-6). b, c, Results are presented in up to 1,281 cases and 860 controls for analyses conditioned on HLA-DRB1 and HLA-DQB1 combined (annotated SNPs were followed up in a larger case–control set; Supplementary Table 6) (b), and for analyses conditioned on HLA-DRB1 and HLA-DQB1 combined and the alleles of HLA-B with frequency >0.01 (c).