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High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

Sun C 1 , Molineros JE 1 , Looger LL 2 , Zhou XJ 3 , Kim K 4 , Okada Y 5 Show all authors , Ma J 6 , Qi YY 3 , Kim-Howard X 1 , Motghare P 1 , Bhattarai K 1 , Adler A 1 , Bang SY 4 , Lee HS 4 , Kim TH 4 , Kang YM 7 , Suh CH 8 , Chung WT 9 , Park YB 10 , Choe JY 11 , Shim SC 12 , Kochi Y 13 , Suzuki A 13 , Kubo M 14 , Sumida T 15 , Yamamoto K 13 , Lee SS 16 , Kim YJ 17 , Han BG 17 , Dozmorov M 18 , Kaufman KM 19 , Wren JD 1 , Harley JB 19 , Shen N 6 , Chua KH 20 , Zhang H 3 , Bae SC 4 , Nath SK 1

Affiliations 

  • 1 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  • 2 Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, USA
  • 3 Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • 4 Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
  • 5 Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  • 6 Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • 7 School of Medicine, Kyungpook National University Hospital, Daegu, Korea
  • 8 Department of Rheumatology, Ajou University Hospital, Suwon, Korea
  • 9 Department of Internal Medicine, Dong-A University Hospital, Busan, Korea
  • 10 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
  • 11 Department of Internal Medicine, Daegu Catholic University Hospital, Daegu, Korea
  • 12 Daejeon Rheumatoid and Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Korea
  • 13 Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
  • 14 Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  • 15 Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  • 16 Department of Rheumatology, Chonnam National University Hospital, Gwangju, Korea
  • 17 Korea National Institute of Health, Osong, Korea
  • 18 Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
  • 19 Department of Pediatrics, Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
  • 20 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Nat Genet, 2016 Mar;48(3):323-30.
PMID: 26808113 DOI: 10.1038/ng.3496

Abstract

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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