Christopher J Lessard1, Satria Sajuthi2, Jian Zhao3, Kwangwoo Kim4, John A Ice1, He Li1,5, Hannah Ainsworth2, Astrid Rasmussen1, Jennifer A Kelly1, Mindy Marion2, So-Young Bang4, Young Bin Joo4, Jeongim Choi4, Hye-Soon Lee4, Young Mo Kang6, Chang-Hee Suh7, Won Tae Chung8, Soo-Kon Lee9, Jung-Yoon Choe10, Seung Cheol Shim11, Ji Hee Oh12, Young Jin Kim12, Bok-Ghee Han12, Nan Shen13,14, Hwee Siew Howe15, Edward K Wakeland16, Quan-Zhen Li16, Yeong Wook Song17, Patrick M Gaffney1, Marta E Alarcón-Riquelme1,18, Lindsey A Criswell19, Chaim O Jacob20, Robert P Kimberly21, Timothy J Vyse22, John B Harley23,24, Kathy L Sivils1,5, Sang-Cheol Bae4, Carl D Langefeld2, Betty P Tsao3. 1. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. 2. Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-106, USA. 3. Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. 4. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea. 5. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA. 6. Kyungpook National University Hospital, Daegu 700-721, Republic of Korea. 7. Ajou University Hospital, Suwon 443-380, Republic of Korea. 8. Dong-A University Hospital, Busan 602-715, Republic of Korea. 9. Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-749, Republic of Korea. 10. Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea. 11. Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon 305-764, Republic of Korea. 12. Korea National Institute of Health, Osong 361-709, Republic of Korea. 13. Shanghai Institute of Rheumatology, Renji Hospital, Shanghai, China 200001. 14. Shanghai JiaoTong University School of Medicine, Shanghai, China 200025. 15. Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433. 16. University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 17. Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. 18. Centro de Genómica e Investigaciones Oncológicas, Pfizer-Universidad de Granada-Junta de Andalućıa, Granada 18100, Spain. 19. Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA, 94117, USA. 20. Department of Medicine, University of Southern California, Los Angeles, CA 90095. 21. Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. 22. Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, King's College London, London, UK WC2R 2LS. 23. Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. 24. US Department of Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
Abstract
OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. METHODS: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. RESULTS: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. CONCLUSION: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.
OBJECTIVE:Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. METHODS: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. RESULTS: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. CONCLUSION: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
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