Human Molecular Genetics Advance Access published online on January 6, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp007
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Evaluation of Imputation-based Association in and around the Integrin-
-M (ITGAM) gene and Replication of Robust Association between a Non-synonymous Functional variant within ITGAM and Systemic lupus erythematosus (SLE)
1 Genetic Epidemiology Unit, Oklahoma Medical Research Foundation, Oklahoma City, OK 2 Arthritis & Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 3 Institute of Medical Science, University of Tokyo, Tokyo, Japan 4 Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 5 Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK 6 US Department of Veterans Affairs Medical Center, Oklahoma City, OK 7 Center for Autoimmune Diseases Research (CREA), Rosario University, Bogota, Colombia 8 Department of Rheumatology, Pediatric Hospital, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico 9 Instituto Nacional de Medicina Genómica, Mexico City, Mexico 10 Rheumatology Section, Imperial College, Hammersmith Hospital, London, United Kingdom 11 Hospital for Rheumatic Diseases, Seoul, South Korea 12 Feinstein Institute for Medical Research, Manhasset, New York 13 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 14 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 15 Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 16 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden 17 Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK
* Address for Correspondence Swapan K. Nath, Ph.D Genetic Epidemiology Unit, Arthritis and Immunology Research Program Oklahoma Medical Research Foundation 1025 N.E. 13th Street Oklahoma City, OK 73104 Phone: 405-271-7765 Fax: 405-271-4110 Email: Swapan-Nath{at}omrf.org
Received November 10, 2008; Revised December 30, 2008; Accepted December 30, 2008
We recently identified a novel non-synonymous variant, rs1143679, at exon-3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EA) and African-Americans. Using genome-wide association approach, 3 other studies also independently reported an association between SLE susceptibility and ITGAM, or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility, and to confirm a robust ITGAM association across 9 independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele "A") with SLE in EA (P = 1.0 x 10–8) and Hispanic-American (P = 2.9 x 10–5). Second, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-HLA susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log10Bayes factor = 20, P = 6.17 x 10–24). Third, we determined the robustness of rs1143679 association with SLE across 3 additional case-control samples, including UK (P = 6.2 x 10–8), Colombian (P = 3.6 x 10–7), Mexican (P = 0.002), as well as 2 independent sets of trios from UK (PTDT =1.4 x 10–5) and Mexico (PTDT =0.015). A meta-analysis combing all independent data sets greatly reinforces the association (Pmeta = 7.1 x 10–50, OR = 1.83, 95%CI = 1.69–1.98, n = 10,046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.
18 Contributed equally
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