PMID- 24656864
OWN - NLM
STAT- MEDLINE
DCOM- 20140530
LR  - 20240109
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 94
IP  - 4
DP  - 2014 Apr 3
TI  - Fine mapping seronegative and seropositive rheumatoid arthritis to shared and 
      distinct HLA alleles by adjusting for the effects of heterogeneity.
PG  - 522-32
LID - S0002-9297(14)00071-8 [pii]
LID - 10.1016/j.ajhg.2014.02.013 [doi]
AB  - Despite progress in defining human leukocyte antigen (HLA) alleles for 
      anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis 
      (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging 
      because of clinical heterogeneity within clinical cohorts. We imputed 8,961 
      classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery 
      set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a 
      statistical approach to identify and adjust for clinical heterogeneity within 
      ACPA(-) RA and observed independent associations for serine and leucine at 
      position 11 in HLA-DRbeta1 (p = 1.4 x 10(-13), odds ratio [OR] = 1.30) and for 
      aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the 
      peptide binding grooves. These amino acid positions induced associations at 
      HLA-DRB1( *)03 (encoding serine at 11) and HLA-B( *)08 (encoding aspartate at 9). 
      We validated these findings in an independent set of 427 ACPA(-) case subjects, 
      carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control 
      subjects (HLA-DRbeta1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 
      x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and 
      ACPA(-) disease, the effects of individual residues at HLA-DRbeta1 position 11 were 
      distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA 
      at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 
      15,870 control subjects. These results contribute to mounting evidence that 
      ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate 
      autoantigens contributing to pathogenesis. We expect that our approach might have 
      broad applications in analyzing clinical conditions with heterogeneity at both 
      major histocompatibility complex (MHC) and non-MHC regions.
CI  - Copyright (c) 2014 The American Society of Human Genetics. Published by Elsevier 
      Inc. All rights reserved.
FAU - Han, Buhm
AU  - Han B
AD  - Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, 
      Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad 
      Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare 
      Center for Personalized Genetic Medicine, Boston, MA 02115, USA.
FAU - Diogo, Dorothee
AU  - Diogo D
AD  - Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, 
      Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad 
      Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare 
      Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of 
      Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard 
      Medical School, Boston, MA, 02115, USA.
FAU - Eyre, Steve
AU  - Eyre S
AD  - Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, 
      University of Manchester, Manchester Academic Health Sciences Centre, Manchester 
      M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central 
      Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health 
      Sciences Centre, Manchester M13 9PT, UK.
FAU - Kallberg, Henrik
AU  - Kallberg H
AD  - Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska 
      University Hospital Solna, 171 76 Stockholm, Sweden.
FAU - Zhernakova, Alexandra
AU  - Zhernakova A
AD  - Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, the 
      Netherlands; Department of Genetics, University Medical Center Groningen and 
      University of Groningen, 9700 RB Groningen, the Netherlands.
FAU - Bowes, John
AU  - Bowes J
AD  - Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, 
      University of Manchester, Manchester Academic Health Sciences Centre, Manchester 
      M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central 
      Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health 
      Sciences Centre, Manchester M13 9PT, UK.
FAU - Padyukov, Leonid
AU  - Padyukov L
AD  - Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska 
      University Hospital Solna, 171 76 Stockholm, Sweden.
FAU - Okada, Yukinori
AU  - Okada Y
AD  - Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, 
      Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad 
      Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare 
      Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of 
      Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard 
      Medical School, Boston, MA, 02115, USA.
FAU - Gonzalez-Gay, Miguel A
AU  - Gonzalez-Gay MA
AD  - Rheumatology Division, Hospital Universitario Marques de Valdecilla, Instituto de 
      Formacion e Investigacion Marques de Valdecilla, 39008 Santander, Spain.
FAU - Rantapaa-Dahlqvist, Solbritt
AU  - Rantapaa-Dahlqvist S
AD  - Department of Public Health and Clinical Medicine and Department of Rheumatology, 
      Umea University, 901 85 Umea, Sweden.
FAU - Martin, Javier
AU  - Martin J
AD  - Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de 
      Investigaciones Cientificas, 18100 Armilla, Granada, Spain.
FAU - Huizinga, Tom W J
AU  - Huizinga TW
AD  - Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, the 
      Netherlands.
FAU - Plenge, Robert M
AU  - Plenge RM
AD  - Merck Research Laboratories, Merck & Co. Inc., Boston, MA 02115, USA.
FAU - Worthington, Jane
AU  - Worthington J
AD  - Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, 
      University of Manchester, Manchester Academic Health Sciences Centre, Manchester 
      M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central 
      Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health 
      Sciences Centre, Manchester M13 9PT, UK.
FAU - Gregersen, Peter K
AU  - Gregersen PK
AD  - The Feinstein Institute for Medical Research, North Shore-Long Island Jewish 
      Health System, Manhasset, NY 11030, USA.
FAU - Klareskog, Lars
AU  - Klareskog L
AD  - Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska 
      University Hospital Solna, 171 76 Stockholm, Sweden.
FAU - de Bakker, Paul I W
AU  - de Bakker PI
AD  - Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, 
      Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad 
      Institute of Harvard and MIT, Cambridge, MA 02142, USA; Departments of 
      Epidemiology and Medical Genetics, University Medical Center Utrecht, 3584 CG 
      Utrecht, the Netherlands.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AD  - Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, 
      Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad 
      Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare 
      Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of 
      Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard 
      Medical School, Boston, MA, 02115, USA; Arthritis Research UK Epidemiology Unit, 
      Musculoskeletal Research Group, University of Manchester, Manchester Academic 
      Health Sciences Centre, Manchester M13 9PT, UK. Electronic address: 
      soumya@broadinstitute.org.
LA  - eng
GR  - 1R01AR062886-01/AR/NIAMS NIH HHS/United States
GR  - K08AR055688/AR/NIAMS NIH HHS/United States
GR  - 1R01AR063759-01A1/AR/NIAMS NIH HHS/United States
GR  - U01 GM092691/GM/NIGMS NIH HHS/United States
GR  - K08 AR055688/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
GR  - R01 AR063759/AR/NIAMS NIH HHS/United States
GR  - R01 AR062886/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140320
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (HLA Antigens)
SB  - IM
MH  - *Alleles
MH  - Arthritis, Rheumatoid/*genetics
MH  - Case-Control Studies
MH  - *Genetic Heterogeneity
MH  - HLA Antigens/*genetics
MH  - Humans
PMC - PMC3980428
EDAT- 2014/03/25 06:00
MHDA- 2014/05/31 06:00
PMCR- 2014/10/03
CRDT- 2014/03/25 06:00
PHST- 2013/12/16 00:00 [received]
PHST- 2014/02/24 00:00 [accepted]
PHST- 2014/03/25 06:00 [entrez]
PHST- 2014/03/25 06:00 [pubmed]
PHST- 2014/05/31 06:00 [medline]
PHST- 2014/10/03 00:00 [pmc-release]
AID - S0002-9297(14)00071-8 [pii]
AID - 10.1016/j.ajhg.2014.02.013 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2014 Apr 3;94(4):522-32. doi: 10.1016/j.ajhg.2014.02.013. Epub 
      2014 Mar 20.