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Nature Research, Nature Genetics, 9(47), p. 1085-1090

DOI: 10.1038/ng.3379

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Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

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This paper is available in a repository.

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Abstract

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552599/ ; © 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 × 10 -12 ; T1D, P = 2.4 × 10 -10 ; psoriasis, P = 5.9 × 10 -6 ; celiac disease, P = 1.2 × 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 × 10 -3 ; T1D, P = 8.6 × 10 -27 ; celiac disease, P = 6.0 × 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.