PMID- 26168013
OWN - NLM
STAT- MEDLINE
DCOM- 20151026
LR  - 20230723
IS  - 1546-1718 (Electronic)
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 47
IP  - 8
DP  - 2015 Aug
TI  - Additive and interaction effects at three amino acid positions in HLA-DQ and 
      HLA-DR molecules drive type 1 diabetes risk.
PG  - 898-905
LID - 10.1038/ng.3353 [doi]
AB  - 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-DQbeta1 position 57 (previously known; P = 1 x 10(-1,355)) by itself explained 
      15.2% of the total phenotypic variance. Independent effects at HLA-DRbeta1 positions 
      13 (P = 1 x 10(-721)) and 71 (P = 1 x 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 x 10(-64)). HLA-DRbeta1 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.
FAU - Hu, Xinli
AU  - Hu X
AD  - 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.
FAU - Deutsch, Aaron J
AU  - Deutsch AJ
AUID- ORCID: 0000000167505335
AD  - 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.
FAU - Lenz, Tobias L
AU  - Lenz TL
AD  - 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, Plon, Germany.
FAU - Onengut-Gumuscu, Suna
AU  - Onengut-Gumuscu S
AD  - Center for Public Health Genomics, University of Virginia, Charlottesville, 
      Virginia, USA.
FAU - Han, Buhm
AU  - Han B
AD  - 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.
FAU - Chen, Wei-Min
AU  - Chen WM
AD  - Center for Public Health Genomics, University of Virginia, Charlottesville, 
      Virginia, USA.
FAU - Howson, Joanna M M
AU  - Howson JM
AD  - Department of Public Health and Primary Care, University of Cambridge, Cambridge, 
      UK.
FAU - Todd, John A
AU  - Todd JA
AD  - 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.
FAU - de Bakker, Paul I W
AU  - de Bakker PI
AD  - 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.
FAU - Rich, Stephen S
AU  - Rich SS
AD  - Center for Public Health Genomics, University of Virginia, Charlottesville, 
      Virginia, USA.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AD  - 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.
LA  - eng
GR  - MR/L003120/1/MRC_/Medical Research Council/United Kingdom
GR  - 5U01GM092691-05/GM/NIGMS NIH HHS/United States
GR  - U01 GM092691/GM/NIGMS NIH HHS/United States
GR  - U01 DK062418/DK/NIDDK NIH HHS/United States
GR  - RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom
GR  - 5R01AR062886-02/AR/NIAMS NIH HHS/United States
GR  - UH2 AR067677/AR/NIAMS NIH HHS/United States
GR  - R01 AR065183/AR/NIAMS NIH HHS/United States
GR  - 100140/WT_/Wellcome Trust/United Kingdom
GR  - 1UH2AR067677-01/AR/NIAMS NIH HHS/United States
GR  - 1R01AR063759/AR/NIAMS NIH HHS/United States
GR  - DH_/Department of Health/United Kingdom
GR  - R01AR065183/AR/NIAMS NIH HHS/United States
GR  - R01 AR063759/AR/NIAMS NIH HHS/United States
GR  - R01 AR062886/AR/NIAMS NIH HHS/United States
GR  - 091157/WT_/Wellcome Trust/United Kingdom
GR  - U01DK062418/DK/NIDDK NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150713
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (Amino Acids)
RN  - 0 (HLA-DQ alpha-Chains)
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DQA1 antigen)
RN  - 0 (HLA-DQB1 antigen)
RN  - 0 (HLA-DRB1 Chains)
SB  - IM
MH  - Algorithms
MH  - Amino Acids/*genetics
MH  - Case-Control Studies
MH  - Diabetes Mellitus, Type 1/*genetics/pathology
MH  - Epistasis, Genetic
MH  - Female
MH  - Genotype
MH  - HLA-DQ alpha-Chains/*genetics
MH  - HLA-DQ beta-Chains/*genetics
MH  - HLA-DRB1 Chains/*genetics
MH  - Haplotypes
MH  - Humans
MH  - Logistic Models
MH  - Male
MH  - Models, Genetic
MH  - Phenotype
MH  - Polymorphism, Single Nucleotide
MH  - Risk Factors
PMC - PMC4930791
MID - NIHMS788834
COIS- COMPETING FINANCIAL INTERESTS The authors declare no competing financial 
      interests.
EDAT- 2015/07/15 06:00
MHDA- 2015/10/27 06:00
PMCR- 2016/07/03
CRDT- 2015/07/14 06:00
PHST- 2015/03/12 00:00 [received]
PHST- 2015/06/17 00:00 [accepted]
PHST- 2015/07/14 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2015/10/27 06:00 [medline]
PHST- 2016/07/03 00:00 [pmc-release]
AID - ng.3353 [pii]
AID - 10.1038/ng.3353 [doi]
PST - ppublish
SO  - Nat Genet. 2015 Aug;47(8):898-905. doi: 10.1038/ng.3353. Epub 2015 Jul 13.