Human Molecular Genetics Advance Access originally published online on January 6, 2009
Human Molecular Genetics 2009 18(6):1171-1180; 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 2 Arthritis and Immunology Program 3 Clinical Immunology Research Program 4 Clinical Pharmacology, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, USA 5 Institute of Medical Science, University of Tokyo, Tokyo, Japan 6 US Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA 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, UK 11 Hospital for Rheumatic Diseases, Seoul, South Korea 12 Feinstein Institute for Medical Research, Manhasset, New York, NY, USA 13 Department of Pathology 14 Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 15 Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA 16 Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA 17 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
* To whom correspondence should be addressed. Tel: +1 4052717765; Fax: +1 4052714110; Email: swapan-nath{at}omrf.org
Received November 10, 2008; Accepted January 2, 2009
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 (EAs) and African-Americans. Using genome-wide association approach, three 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 nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele ‘A’) with SLE in EAs (P = 1.0 x 10–8) and Hispanic-Americans (P = 2.9 x 10–5). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen 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). Thirdly, we determined the robustness of rs1143679 association with SLE across three 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 two 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, odds ratio = 1.83, 95% confidence interval = 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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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