Journal Article

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

Klareskog, Lars, Rich, Stephen S, Wijmenga, Cisca, Gregersen, Peter K, Abecasis, Gonçalo, Boeckxstaens, Guy E, Worthington, Jane, Becker, Jessica, Nair, Rajan P, de Bakker, Paul I W, Deutsch, Aaron J, Stuart, Philip E, Gutierrez-Achury, Javier, Eyre, Stephen, Han, Buhm, Nöthen, Markus M, Tsoi, Lam C, Raychaudhuri, Soumya, Huizinga, Tom W J, Gockel, Ines, Wouters, Mira M, Chen, Wei-Min, Sunyaev, Shamil R, Gladman, Dafna D, Hu, Xinli, Rantapää-Dahlqvist, Solbritt, Franke, Andre, Martin, Javier, Knapp, Michael, Schumacher, Johannes, Rahman, Proton, Okada, Yukinori, Lenz, Tobias L, Elder, James T, Zhernakova, Alexandra, Onengut-Gumuscu, Suna, van Heel, David A

2015

Overview

Soumya Raychaudhuri, Paul de Bakker and colleagues test the non-additive disease contributions of classical HLA alleles to five common autoimmune diseases. In four of the five diseases, they observe highly significant non-additive dominance and interaction effects. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/43 / 631/208/248 / 631/208/457 / 631/250/248 / Agriculture / Animal Genetics and Genomics / Antigens / Autoimmune diseases / Autoimmune Diseases - genetics / Biomedicine / Cancer Research / Case-Control Studies / Celiac disease / Datasets / Disease / Epistasis, Genetic / Gene Function / Genetic aspects / Genetic Association Studies / Genetic Loci / Genetic Predisposition to Disease / Haplotypes / Health aspects / Health risks / Histocompatibility antigens / Histocompatibility Antigens Class I - genetics / HLA histocompatibility antigens / HLA-C Antigens - genetics / HLA-D Antigens - genetics / Human Genetics / Humans / letter / Polymorphism, Single Nucleotide / Psoriasis / Rheumatoid arthritis / Risk Factors / Single nucleotide polymorphisms / Skin diseases / Studies