Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Hu, X, Deutsch, AJ, Lenz, TL, Onengut-Gumuscu, S, Han, B, Chen, W-M, Howson, JMM, Todd, JA, de Bakker, PIW, Rich, SS, Raychaudhuri, S |
Journal | Nat Genet |
Volume | 47 |
Issue | 8 |
Pages | 898-905 |
Date Published | 2015 Aug |
ISSN | 1546-1718 |
Keywords | Algorithms, 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. |
URL | http://dx.doi.org/10.1038/ng.3353 |
DOI | 10.1038/ng.3353 |
Pubmed | |
Alternate Journal | Nat. Genet. |
PubMed ID | 26168013 |
PubMed Central ID | PMC4930791 |
Grant List | 5U01GM092691-05 / 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 |
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.
Recent Broad Publications
News at the broad
News / 01.30.23
News / 01.12.23
News / 01.18.23