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In this study, the combined risk for expressing anti-islet autoantibodies and type 1A diabetes (T1D) was prospectively examined in 85 sampled relatives who had the high-risk HLA genotype (DR3-DQ8 DR4-DQ2). An insulin gene polymorphism, -23 HphI, and a lymphocyte tyrosine phosphatase gene polymorphism at position 1858C>T (amino acid 620 Arg to Trp), PTPN22/LYP, were analyzed. Life tables were created evaluating time to anti-islet autoantibody development and T1D. Of relatives with the high-risk HLA type followed for 3years, 9 of 43 (28.1%) with the high-risk -23 HphI polymorphism developed anti-islet autoantibodies versus two of 36 (5.6%) relatives with the lower-risk -23 HphI genotypes (p=0.048). Of relatives with the high-risk HLA type followed for 5years, eight of 32 (25.0%) with the high-risk -23 HphI polymorphism (A/A) developed T1D versus zero of 26 (0%) relatives with the lower-risk -23 HphI genotypes (A/T and T/T) (p=0.006). The PTPN22/LYP polymorphism, with genotypes C/C, C/T, and T/T, did not show a significant difference in risk by genotype. These results highlight the multiplicative risk of combined high-risk genotypes at different loci in terms of time to autoantibody and autoimmune disease development.

A total of 21,000 general population newborns (NECs) and 693 young siblings-offspring of patients with type 1A diabetes (SOCs) were class II genotyped and 293 NECs and 72 SOCs with the high-risk genotype, DR3/4, DQB1*0302 have been prospectively evaluated. Seventeen individuals who converted to persistent autoantibody positivity and two autoantibody-negative control groups (35 SOCs and 24 NECs) were typed for HLA-A class I alleles. The A1, A2 genotype was significantly increased among the autoantibody-positive subjects (47%) compared to autoantibody-negative SOCs (14%, P = 0.01) and NECs (13%, P = 0.02). Life-table analysis of DR3/4, DQB1*0302 siblings revealed a risk of 75% for development of islet autoantibodies by the age of 2 years for those with A1, A2. The HLA-A2 phenotype frequency was increased among an independent DR3/4, DQB1*0302 young diabetes cohort (64% versus 33% for autoantibody-negative NECs). These results suggest that a high incidence and early appearance of islet autoantibodies for siblings of patients with type 1A diabetes are associated with DR3/4, DQB1*0302 and potentially increased with HLA-A genotype A1, A2.