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Nat Genet. 2015 Aug;47(8):898-905. doi: 10.1038/ng.3353. Epub 2015 Jul 13.

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

Author information

1
1] Department of Medicine, Brigham and Women's Hospital, Division of Rheumatology, Immunology and Allergy, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital, Division of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [3] Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA. [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [5] Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA. [6] Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
2
1] Department of Medicine, Brigham and Women's Hospital, Division of Rheumatology, Immunology and Allergy, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital, Division of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [3] Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA. [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [5] Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA.
3
1] Department of Medicine, Brigham and Women's Hospital, Division of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [2] Evolutionary Immunogenomics, Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Plön, Germany.
4
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
5
1] Department of Medicine, Brigham and Women's Hospital, Division of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [3] Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
6
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
7
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
8
1] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
9
1] Department of Medicine, Brigham and Women's Hospital, Division of Rheumatology, Immunology and Allergy, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital, Division of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [3] Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA. [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [5] Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

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.

PMID:
26168013
PMCID:
PMC4930791
DOI:
10.1038/ng.3353
[Indexed for MEDLINE]
Free PMC Article

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