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 x 10(-11)) and B*3906 (10.31; P = 4 X 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 H. Other class I type 1 diabetes associations appear to be specific to individual class H 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 H alleles, are associated with type 1 diabetes. Diabetes 59:2972-2979, 201

HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes: Analysis of the Type 1 Diabetes Genetics Consortium Families

OBJECTIVE-To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type I diabetes. RESEARCH DESIGN AND METHODS-The frequency of DPA1 and DPB1 alleles and haplotypes in type I diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on FILA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined. RESULTS-Eight DPAI and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed, nineteen DPB1 alleles were associated with multiple DPA1 alleles Following both analyses, type I diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype CONCLUSIONS-HLA DP allelic and haplotypic diversity contributes significantly to the risk for type I diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes Diabetes 59:2055-2062, 201

HLA genotyping in the international Type 1 Diabetes Genetics Consortium

Background Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers