Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk
Hu, Xinli; Deutsch, Aaron J; Lenz, Tobias L; Onengut-Gumuscu, Suna; Han, Buhm; Chen, Wei-Min; Howson, Joanna M M; Todd, John A; de Bakker, Paul I W; Rich, Stephen S; Raychaudhuri, Soumya
(2015) Nature Genetics, volume 47, issue 8, pp. 898 - 905
(Article)
Abstract
Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized
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the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10(-1,355)) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10(-721)) and 71 (P = 1 × 10(-95)) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1-HLA-DQA1-HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1-HLA-DQA1-HLA-DQB1 haplotypes (P = 1.6 × 10(-64)). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.
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Keywords: Algorithms, Amino Acids, Case-Control Studies, Diabetes Mellitus, Type 1, Epistasis, Genetic, Female, Genotype, HLA-DQ alpha-Chains, HLA-DQ beta-Chains, HLA-DRB1 Chains, Haplotypes, Humans, Logistic Models, Male, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN: 1061-4036
Publisher: Nature Publishing Group
(Peer reviewed)