Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study |
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| Authors: | Lessard Christopher J Adrianto Indra Kelly Jennifer A Kaufman Kenneth M Grundahl Kiely M Adler Adam Williams Adrienne H Gallant Caroline J;Marta E Alarcón-Riquelme on behalf of the BIOLUPUS and GENLES Networks Anaya Juan-Manuel Bae Sang-Cheol Boackle Susan A Brown Elizabeth E Chang Deh-Ming Criswell Lindsey A Edberg Jeffrey C Freedman Barry I Gregersen Peter K Gilkeson Gary S Jacob Chaim O James Judith A Kamen Diane L Kimberly Robert P Martin Javier Merrill Joan T Niewold Timothy B Park So-Yeon Petri Michelle A Pons-Estel Bernardo A Ramsey-Goldman Rosalind Reveille John D Song Yeong Wook |
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| Institution: | 1Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA;2Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;3US Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA;4Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA;5Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75105, Sweden;6Center for Genomics and Oncological Research, Granada 18100, Spain;7Center for Autoimmune Diseases Research, Universidad del Rosario, Bogota 111221, Colombia;8Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-799, Korea;9Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA;10Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;11National Defense Medical Center, Taipei 114, Taiwan;12Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, CA 94143, USA;13Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;14Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA;15The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA;16Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29403, USA;17Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA;18Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;19Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, Granada 18100, Spain;20Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA;21Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA;22Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;23Sanatorio Parque, Rosario 2000, Argentina;24Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;25Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;26Division of Rheumatology, Seoul National University, Seoul 110-799, Korea;27Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, WA 98105, USA;28Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98105, USA;29Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA;30Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan 00936-5067, Puerto Rico;31Division of Medicine, Imperial College of London, London W12 0NN, UK;32Center for Molecular and Human Genetics, Research Institute at National Children's Hospital, Columbus, OH 43205, USA;33Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA;34Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA |
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| Abstract: | Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10(-8), OR = 0.83) and rs387619 (p = 7.7 × 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 × 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10(-3), OR = 0.81 and p = 4.3 × 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 × 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex. |
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