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High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci
  1. Kwangwoo Kim1,2,3,4,
  2. So-Young Bang1,
  3. Hye-Soon Lee1,
  4. Soo-Kyung Cho1,
  5. Chan-Bum Choi1,
  6. Yoon-Kyoung Sung1,
  7. Tae-Hwan Kim1,
  8. Jae-Bum Jun1,
  9. Dae Hyun Yoo1,
  10. Young Mo Kang5,
  11. Seong-Kyu Kim6,
  12. Chang-Hee Suh7,
  13. Seung-Cheol Shim8,
  14. Shin-Seok Lee9,
  15. Jisoo Lee10,
  16. Won Tae Chung11,
  17. Jung-Yoon Choe6,
  18. Hyoung Doo Shin12,
  19. Jong-Young Lee13,
  20. Bok-Ghee Han13,
  21. Swapan K Nath14,
  22. Steve Eyre15,
  23. John Bowes15,
  24. Dimitrios A Pappas16,
  25. Joel M Kremer17,
  26. Miguel A Gonzalez-Gay18,
  27. Luis Rodriguez-Rodriguez19,
  28. Lisbeth Ärlestig20,
  29. Yukinori Okada2,3,4,21,22,
  30. Dorothée Diogo2,3,4,
  31. Katherine P Liao2,
  32. Elizabeth W Karlson2,
  33. Soumya Raychaudhuri2,3,4,15,
  34. Solbritt Rantapää-Dahlqvist20,
  35. Javier Martin23,
  36. Lars Klareskog24,
  37. Leonid Padyukov24,
  38. Peter K Gregersen25,
  39. Jane Worthington14,
  40. Jeffrey D Greenberg26,
  41. Robert M Plenge2,3,4,
  42. Sang-Cheol Bae1
  1. 1Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
  2. 2Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  4. 4Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
  5. 5Division of Rheumatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
  6. 6Division of Rheumatology, Department of Internal Medicine, Arthritis & Autoimmunity Research Center, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
  7. 7Department of Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea
  8. 8Division of Rheumatology, Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Republic of Korea
  9. 9Division of Rheumatology, Department of Internal Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
  10. 10Division of Rheumatology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea
  11. 11Division of Rheumatology, Department of internal medicine, Dong-A University, Busan, Republic of Korea
  12. 12Department of Life Science, Sogang University, Seoul, Republic of Korea
  13. 13Center for Genome Science, Korea National Institute of Health, Osong Health Technology, Chungcheongbuk-do, Republic of Korea
  14. 14Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  15. 15Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
  16. 16Department of Medicine, Division of Rheumatology, Columbia University, New York, New York, USA
  17. 17The Center of Rheumatology, Albany, New York, USA
  18. 18Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain
  19. 19Department of Rheumatology, Hospital Clinico San Carlos, Madrid, Spain
  20. 20Department of Clinical Medicine/Rheumatoloy, Umeå University, Umeå, Sweden
  21. 21Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  22. 22Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  23. 23Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain
  24. 24Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
  25. 25The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York, USA
  26. 26Division of Rheumatology, New York University School of Medicine, New York, New York, USA
  1. Correspondence to Dr Robert M Plenge, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; rplenge{at}partners.org or Dr Sang-Cheol Bae, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea; scbae{at}hanyang.ac.kr

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.

  • Rheumatoid Arthritis
  • Gene Polymorphism
  • Ant-CCP

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