Genetic prediction of autoimmunity: Initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4–DQ8 relatives of patients with type 1A diabetes

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), PTPN 22/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 3 years, 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 5 years, 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 PTPN 22/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.