Nature Research, Nature Genetics, 9(47), p. 1085-1090
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552599/ ; Â© 2015 Nature America, Inc. All rights reserved.Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (n cases = 5,337), type 1 diabetes (T1D; n cases = 5,567), psoriasis vulgaris (n cases = 3,089), idiopathic achalasia (n cases = 727) and celiac disease (n cases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 Ã— 10 -12 ; T1D, P = 2.4 Ã— 10 -10 ; psoriasis, P = 5.9 Ã— 10 -6 ; celiac disease, P = 1.2 Ã— 10 -87 ). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 Ã— 10 -3 ; T1D, P = 8.6 Ã— 10 -27 ; celiac disease, P = 6.0 Ã— 10 -100 ). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.