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Nat Genet DOI:10.1038/ng.3353

Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.

Publication TypeJournal Article
Year of Publication2015
AuthorsHu, X, Deutsch, AJ, Lenz, TL, Onengut-Gumuscu, S, Han, B, Chen, W-M, Howson, JMM, Todd, JA, de Bakker, PIW, Rich, SS, Raychaudhuri, S
JournalNat Genet
Volume47
Issue8
Pages898-905
Date Published2015 Aug
ISSN1546-1718
KeywordsAlgorithms, Amino Acids, Case-Control Studies, Diabetes Mellitus, Type 1, Epistasis, Genetic, Female, Genotype, Haplotypes, HLA-DQ alpha-Chains, HLA-DQ beta-Chains, HLA-DRB1 Chains, Humans, Logistic Models, Male, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide, Risk Factors
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 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.

URLhttp://dx.doi.org/10.1038/ng.3353
DOI10.1038/ng.3353
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26168013?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID26168013
PubMed Central IDPMC4930791
Grant List5U01GM092691-05 / GM / NIGMS NIH HHS / United States
RG/08/014/24067 / / British Heart Foundation / United Kingdom
R01AR065183 / AR / NIAMS NIH HHS / United States
/ / Department of Health / United Kingdom
MR/L003120/1 / / Medical Research Council / United Kingdom
U01 GM092691 / GM / NIGMS NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
5R01AR062886-02 / AR / NIAMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
R01 AR062886 / AR / NIAMS NIH HHS / United States
UH2 AR067677 / AR / NIAMS NIH HHS / United States
R01 AR065183 / AR / NIAMS NIH HHS / United States
091157 / / Wellcome Trust / United Kingdom
U01DK062418 / DK / NIDDK NIH HHS / United States
100140 / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
1UH2AR067677-01 / AR / NIAMS NIH HHS / United States
1R01AR063759 / AR / NIAMS NIH HHS / United States