HLA Class I and Genetic Susceptibility to Type 1 Diabetes: Results From the Type 1 Diabetes Genetics Consortium

OBJECTIVE

We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study.

RESEARCH DESIGN AND METHODS

Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients.

RESULTS

Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes–associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10⁻¹¹) and B*3906 (10.31; P = 4 × 10⁻¹⁰). Other significantly type 1 diabetes–associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403).

CONCLUSIONS

These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.Type 1 diabetes is an autoimmune disease characterized by progressive T-cell–mediated destruction of the pancreatic β-cells. Both genetic and environmental factors are involved in disease susceptibility; the major genetic susceptibility determinants are the highly polymorphic HLA loci on chromosome 6p21—more specifically the class II loci, HLA-DRB1, HLA-DQB1/DQA1 (see the study by Erlich et al. [1] and references therein), and, to a lesser extent, HLA-DPB1/DPA1 (2–6). These genes, however, cannot completely explain the association between type 1 diabetes and the HLA region. Several studies have shown that HLA class I genes (A, B, and C) are associated with type 1 diabetes (7–11). Products of the HLA class I genes bind and present peptide antigens. The HLA class I/peptide antigen complexes function both in shaping the T-cell repertoire in the thymus and in initiating antigen-specific T-cell–mediated cytotoxicity, providing a plausible immunological rationale to explain the genetic association. The extremely high linkage disequilibrium (LD) within the HLA region, combined with the strong susceptibility effects of the HLA DR- and DQ-encoding loci, can confound association studies of any loci in the region. Thus, apparent susceptibility effects of HLA class I alleles may, in some cases, be attributable to their presence on highly protective or predisposing HLA DRB1-DQA1-DQB1 haplotypes.Compared with the hundreds of studies of HLA class II association with type 1 diabetes, only a handful of reports focus on HLA class I and type 1 diabetes (7–12), and only a subset of these include molecular genotyping and consideration of LD with class II in association analyses. Some alleles have appeared consistently associated with type 1 diabetes both at the serologic and allele level, including A*24(02) and B*39(06), with and without conditioning on DR-DQ. HLA class I loci are extremely polymorphic, with a total of 2,893 alleles assigned for the three loci as of October 2009. Thus, large sample sizes are crucial to generate sufficient class I data for adequately powered disease association studies. The Type 1 Diabetes Genetics Consortium (T1DGC) is an international collaborative project that has ascertained the largest set of multiplex type 1 diabetes families in existence for the study of the genetic basis of type 1 diabetes susceptibility. All samples collected by the T1DGC are genotyped at all classical HLA loci (DRB1, DQA1, DQB1, DPA1, DPB1, A, B, and C) as well as for single nucleotide polymorphisms (SNPs) in the insulin and CTLA4 genes that have repeatedly been shown to be associated with type 1 diabetes. Subsets of the T1DGC collection have been genotyped for candidate gene SNPs reported to be associated with type 1 diabetes (the “Rapid Response” project), genome-wide microsatellites, and genome-wide SNPs (www.T1DGC.org).