PMID- 25070946
OWN - NLM
STAT- MEDLINE
DCOM- 20150713
LR  - 20221207
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 23
IP  - 25
DP  - 2014 Dec 20
TI  - Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid 
      polymorphisms in Asian and European populations.
PG  - 6916-26
LID - 10.1093/hmg/ddu387 [doi]
AB  - Previous studies have emphasized ethnically heterogeneous human leukocyte antigen 
      (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We 
      fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 
      2782 seropositive RA cases and 4315 controls of Asian descent. We applied 
      imputation to determine genotypes for eight class I and II HLA genes to Asian 
      populations for the first time using a newly constructed pan-Asian reference 
      panel. First, we empirically measured high imputation accuracy in Asian samples. 
      Then we observed the most significant association in HLA-DRbeta1 at amino acid 
      position 13, located outside the classical shared epitope (Pomnibus = 6.9 x 
      10(-135)). The individual residues at position 13 have relative effects that are 
      consistent with published effects in European populations (His > Phe > Arg > Tyr 
       congruent with Gly > Ser)--but the observed effects in Asians are generally smaller. Applying 
      stepwise conditional analysis, we identified additional independent associations 
      at positions 57 (conditional Pomnibus = 2.2 x 10(-33)) and 74 (conditional 
      Pomnibus = 1.1 x 10(-8)). Outside of HLA-DRbeta1, we observed independent effects 
      for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 x 10(-6)) 
      and HLA-DPbeta1 (Phe9, conditional P = 3.0 x 10(-5)) concordant with European 
      populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common 
      set of amino acid residues confer shared effects in European and Asian 
      populations and (ii) these same effects can explain ethnically heterogeneous 
      classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency 
      differences between populations. Our study illustrates the value of 
      high-resolution imputation for fine-mapping causal variants in the MHC.
CI  - (c) The Author 2014. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Okada, Yukinori
AU  - Okada Y
AD  - Department of Human Genetics and Disease Diversity, Graduate School of Medical 
      and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan Laboratory 
      for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 
      Yokohama, Japan Division of Rheumatology, Immunology, and Allergy and Division of 
      Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 
      Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
FAU - Kim, Kwangwoo
AU  - Kim K
AD  - Division of Rheumatology, Immunology, and Allergy and Division of Genetics, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Program in 
      Medical and Population Genetics, Broad Institute, Cambridge, MA, USA Department 
      of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South 
      Korea.
FAU - Han, Buhm
AU  - Han B
AD  - Division of Rheumatology, Immunology, and Allergy and Division of Genetics, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Program in 
      Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
FAU - Pillai, Nisha E
AU  - Pillai NE
AD  - Saw Swee Hock School of Public Health.
FAU - Ong, Rick T-H
AU  - Ong RT
AD  - Saw Swee Hock School of Public Health.
FAU - Saw, Woei-Yuh
AU  - Saw WY
AD  - Saw Swee Hock School of Public Health.
FAU - Luo, Ma
AU  - Luo M
AD  - Department of Medical Microbiology, University of Manitoba, Winnepeg, Canada 
      National Microbiology Laboratory, Winnipeg, Canada.
FAU - Jiang, Lei
AU  - Jiang L
AD  - Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The 
      Second Military Medical University, Shanghai, China.
FAU - Yin, Jian
AU  - Yin J
AD  - Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The 
      Second Military Medical University, Shanghai, China.
FAU - Bang, So-Young
AU  - Bang SY
AD  - Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 
      Seoul, South Korea.
FAU - Lee, Hye-Soon
AU  - Lee HS
AD  - Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 
      Seoul, South Korea.
FAU - Brown, Matthew A
AU  - Brown MA
AD  - The University of Queensland Diamantina Institute, Translational Research 
      Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, 
      Australia.
FAU - Bae, Sang-Cheol
AU  - Bae SC
AD  - Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 
      Seoul, South Korea.
FAU - Xu, Huji
AU  - Xu H
AD  - Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The 
      Second Military Medical University, Shanghai, China.
FAU - Teo, Yik-Ying
AU  - Teo YY
AD  - Saw Swee Hock School of Public Health Life Sciences Institute Department of 
      Statistics and Applied Probability and NUS Graduate School for Integrative 
      Science and Engineering, National University of Singapore, Singapore, Singapore 
      Genome Institute of Singapore, Agency for Science, Technology and Research, 
      Singapore, Singapore.
FAU - de Bakker, Paul I W
AU  - de Bakker PI
AD  - Department of Medical Genetics, Center for Molecular Medicine and Department of 
      Epidemiology, Julius Center for Health Sciences and Primary Care, University 
      Medical Center Utrecht, Utrecht, The Netherlands and.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AD  - Division of Rheumatology, Immunology, and Allergy and Division of Genetics, 
      Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Program in 
      Medical and Population Genetics, Broad Institute, Cambridge, MA, USA NIHR 
      Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS 
      Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 
      soumya@broadinstitute.org.
LA  - eng
GR  - 1R01AR062886-01/AR/NIAMS NIH HHS/United States
GR  - 1R01AR063759-01A1/AR/NIAMS NIH HHS/United States
GR  - R01 AR063759/AR/NIAMS NIH HHS/United States
GR  - MANMKBRU-2012-1/DH_/Department of Health/United Kingdom
GR  - 5U01GM092691-04/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140728
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Amino Acids)
RN  - 0 (Autoantibodies)
RN  - 0 (Epitopes)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-DP beta-Chains)
RN  - 0 (HLA-DPB1 antigen)
RN  - 0 (HLA-DRB1 Chains)
RN  - 29VT07BGDA (Citrulline)
SB  - IM
MH  - Alleles
MH  - Amino Acids/genetics/immunology
MH  - Arthritis, Rheumatoid/*ethnology/*genetics/immunology/pathology
MH  - Asian People
MH  - Autoantibodies/biosynthesis
MH  - Chromosome Mapping
MH  - Citrulline/immunology
MH  - Epitopes/chemistry/immunology
MH  - Gene Expression
MH  - Gene Frequency
MH  - HLA-B Antigens/*genetics/immunology
MH  - HLA-DP beta-Chains/*genetics/immunology
MH  - HLA-DRB1 Chains/*genetics/immunology
MH  - Humans
MH  - *Polymorphism, Genetic
MH  - Risk
MH  - White People
PMC - PMC4245039
EDAT- 2014/07/30 06:00
MHDA- 2015/07/15 06:00
PMCR- 2015/12/20
CRDT- 2014/07/30 06:00
PHST- 2014/07/30 06:00 [entrez]
PHST- 2014/07/30 06:00 [pubmed]
PHST- 2015/07/15 06:00 [medline]
PHST- 2015/12/20 00:00 [pmc-release]
AID - ddu387 [pii]
AID - 10.1093/hmg/ddu387 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2014 Dec 20;23(25):6916-26. doi: 10.1093/hmg/ddu387. Epub 2014 Jul 
      28.