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

• Published in: Journal of autoimmunity 2005, Vol.25, p.40-45
• Main Authors: Aly, Theresa A., Ide, Akane, Humphrey, Kurt, Barker, Jennifer M., Steck, Andrea, Erlich, Henry A., Yu, Liping, Miao, Dongmei, Redondo, Maria J., McFann, Kim, Roberts, Christine M., Babu, Sunanda R., Norris, Jill M., Eisenbarth, George S., Rewers, Marian J.
• Format: Article
• Language: English
• Subjects: Adolescent; Autoimmunity - genetics; Biological and medical sciences; Child; Child, Preschool; Diabetes Mellitus, Type 1 - genetics; Family Health; Fundamental and applied biological sciences. Psychology; Fundamental immunology; General aspects; Genetic susceptibility; Genetic Testing; HLA-DQ Antigens - genetics; HLA-DR Antigens - genetics; Human leukocyte antigen; Humans; Immunopathology; Infant; Infant, Newborn; Insulin gene; Islets of Langerhans - immunology; Lymphocyte tyrosine phosphatase gene; Medical sciences; Polymorphism, Genetic; Predictive Value of Tests; Type 1A diabetes
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2005.09.002

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.