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Association of Toll-like Receptor 4 Variants and Ankylosing Spondylitis: A Case-Control Study
TARA SNELGROVE, SOOYEOL LIM, CELIA GREENWOOD, LYNETTE PEDDLE, SEAN HAMILTON, ROBERT INMAN, and PROTON RAHMAN ABSTRACT. Objective. Functional single nucleotide polymorphisms within the ectoplasmic domain of the Toll-like receptor 4 (TLR4) gene have been shown to result in an endotoxin-hyporesponsive phenotype and aberrant signal transduction for bacterial agonists. TLR4 is in proximity to a genome-wide linkage peak in 9q32-33. Given the proposed function and location of TLR4, we examined the association of 2 functional variants of TLR4 in patients with ankylosing spondylitis (AS) in Newfoundland. Methods. In total, 101 AS patients and 100 ethnically matched controls were genotyped, using the Sequenom MassArray platform, for 2 functional variants in the TLR4 gene: Asp299Gly (A/G polymorphism) and Thr399Ile (C/T polymorphism). Results. The minor allele frequency for the Asp299Gly variant (G) was significantly higher in AS cases compared to controls (7.5% vs 2.6%, respectively; OR 3.10, p = 0.037). The minor allele frequency for the Thr399Ile variant (T) for cases and controls was 7.4% vs 3.0% (OR 2.59, p = 0.071). Haplotype analysis using Haploview noted a higher proportion of GT in the cases (for GT, chi-squared p = 0.023). Conclusion. Given the functional role of TLR4 variants in the innate immune system, larger studies are now warranted to elucidate the association of TLR4 variants in AS. (First Release Dec 1 2006; J Rheumatol 2007;34:368–70) Key Indexing Terms:
ANKYLOSING SPONDYLITIS From the Memorial University of Newfoundland, St. John's, Newfoundland; Genetics and Genomic Biology, Hospital for Sick Children, Department of Public Health Science, University of Toronto; and Department of Medicine and Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Supported by The Arthritis Society and the Canadian Institute of Health Research. T. Snelgrove, MSc, Medical Student, Memorial University; S. Lim, MSc, Biostatistician; C.M.T. Greenwood, PhD, Project Director, Program in Genetics and Genomic Biology, Hospital for Sick Children; L. Peddle, BSc, Senior Laboratory Scientist; S. Hamilton, MD, FRCPC, Associate Professor of Medicine, Memorial University; R.D. Inman, MD, FRCPC, Professor, Departments of Medicine and Immunology, University of Toronto; P. Rahman, MD, MSc, FRCPC, Associate Professor of Medicine, Memorial University. Address reprint requests to Dr. P. Rahman, St. Clare's Mercy Hospital, 1 South–154 LeMarchant Road, St. John's, Newfoundland A1C 5B8, Canada. E-mail: prahman@mun.ca Accepted for publication September 29, 2006.
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