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Ann Rheum Dis. 2015 Mar;74(3):e13. doi: 10.1136/annrheumdis-2013-204749. Epub 2014 Feb 14.

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

Author information

1
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
2
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
3
Division of Rheumatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
4
Division of Rheumatology, Department of Internal Medicine, Arthritis & Autoimmunity Research Center, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
5
Department of Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea.
6
Division of Rheumatology, Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Republic of Korea.
7
Division of Rheumatology, Department of Internal Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
8
Division of Rheumatology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea.
9
Division of Rheumatology, Department of internal medicine, Dong-A University, Busan, Republic of Korea.
10
Department of Life Science, Sogang University, Seoul, Republic of Korea.
11
Center for Genome Science, Korea National Institute of Health, Osong Health Technology, Chungcheongbuk-do, Republic of Korea.
12
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
13
Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
14
Department of Medicine, Division of Rheumatology, Columbia University, New York, New York, USA.
15
The Center of Rheumatology, Albany, New York, USA.
16
Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain.
17
Department of Rheumatology, Hospital Clinico San Carlos, Madrid, Spain.
18
Department of Clinical Medicine/Rheumatoloy, Umeå University, Umeå, Sweden.
19
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA 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.
20
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
21
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
22
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
23
Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
24
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
25
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
26
Division of Rheumatology, New York University School of Medicine, New York, New York, USA.

Abstract

OBJECTIVE:

A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data.

METHODS:

We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples.

RESULTS:

We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs.

CONCLUSIONS:

This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

KEYWORDS:

Ant-CCP; Gene Polymorphism; Rheumatoid Arthritis

PMID:
24532676
PMCID:
PMC4467986
DOI:
10.1136/annrheumdis-2013-204749
[Indexed for MEDLINE]
Free PMC Article
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