title: Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lessard
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-106, USA.
authors.forename: Satria
authors.initials: S
authors.lastname: Sajuthi
authors.affiliation: Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Kim
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Ice
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.|Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-106, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Ainsworth
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Rasmussen
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-106, USA.
authors.forename: Mindy
authors.initials: M
authors.lastname: Marion
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Bang
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Joo
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: Jeongim
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Kyungpook National University Hospital, Daegu 700-721, Republic of Korea.
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
authors.affiliation: Ajou University Hospital, Suwon 443-380, Republic of Korea.
authors.forename: Chang-Hee
authors.initials: CH
authors.lastname: Suh
authors.affiliation: Dong-A University Hospital, Busan 602-715, Republic of Korea.
authors.forename: Won Tae
authors.initials: WT
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-749, Republic of Korea.
authors.forename: Soo-Kon
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Choe
authors.affiliation: Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon 305-764, Republic of Korea.
authors.forename: Seung Cheol
authors.initials: SC
authors.lastname: Shim
authors.affiliation: Korea National Institute of Health, Osong 361-709, Republic of Korea.
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Korea National Institute of Health, Osong 361-709, Republic of Korea.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Korea National Institute of Health, Osong 361-709, Republic of Korea.
authors.forename: Bok-Ghee
authors.initials: BG
authors.lastname: Han
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, Shanghai, China 200001.|Shanghai JiaoTong University School of Medicine, Shanghai, China 200025.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433.
authors.forename: Hwee Siew
authors.initials: HS
authors.lastname: Howe
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea.
authors.forename: Yeong Wook
authors.initials: YW
authors.lastname: Song
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.|Centro de Genómica e Investigaciones Oncológicas, Pfizer-Universidad de Granada-Junta de Andalućıa, Granada 18100, Spain.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA, 94117, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, CA 90095.
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.affiliation: Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, King's College London, London, UK WC2R 2LS.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.|US Department of Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.|Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Sivils
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-106, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
mesh_terms: D044466:Asian People / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D053278:OX40 Ligand / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics*; D056910:Republic of Korea; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C479761:FCHSD2 protein, human; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D008565:Membrane Proteins; D053278:OX40 Ligand; C546385:P2RY2 protein, human; D058473:Receptors, Purinergic P2Y2; C089251:TNFSF4 protein, human; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3