title: Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.
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.
authors.affiliation: 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.
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Aaron J
authors.identifier: 0000000167505335
authors.initials: AJ
authors.lastname: Deutsch
authors.affiliation: 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.
authors.forename: Tobias L
authors.initials: TL
authors.lastname: Lenz
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: 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.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.affiliation: 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.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: 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.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: 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.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000235:genetics*; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D000596:Amino Acids; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains