A STUDY OF TOLL-LIKE RECEPTOR 4 VARIANTS IN ANKYLOSING SPONDYLITIS IN FINNISH FAMILIES

Background: Binding of bacterial lipopolysaccharide to toll-like receptor 4 (TLR4) activates the nuclear factor-κB pathway leading to the up-regulation of pro-inflammatory cytokines. The genes for members of this pathway are therefore plausible candidates for ankylosing spondylitis (AS). Coding variants in TLR4 are associated with susceptibility to AS in a Canadian population (1) but not in a Dutch population (2).Objectives: To investigated the role of TLR4 variants for susceptibility to AS in Finnish families.Methods: The TLR4 D299G (rs4986790, A→G) and T399I (rs4986791, C→T) variants were genotyped in 297 Finnish AS families recruited from the Rheumatism Foundation Hospital, Heinola, Finland. Most families have at least one parent and/or additional siblings. Probands satisfied the modified New York criteria for AS. Mendelian inconsistencies were checked with the program PEDCHECK v1.1 (3). Association analysis was carried out using the program TRANSMIT v2.5 (4). Our study had greater than 80% power to observe an effect comparable to that seen in the Canadian study at the 5% significance level.Results: Neither the D299G nor the T399I variant showed a significant association with susceptibility to AS (P>0.05). When the D299G/T399I haplotype was analysed, a small significant over transmission of the D/T (AC) haplotype was noted (global P=0.03) whereas the Canadian study showed a small association with the G/I (GT) haplotypeConclusion: We were unable to replicate the association of either the D299G variant (G allele) or the GT haplotype seen in Canadian AS cases. Our haplotype analysis indicates a limited association of wild type alleles with AS which suggests that neither of these variants plays a significant role in AS in a Finnish population. This result supports that of the Dutch and highlights population differences between the Canadian and Finnish cohorts.References: 1. Snelgrove T et al., (2007). Association of Toll-like Receptor 4 Variants and Ankylosing Spondylitis: A Case-Control Study. J. Rheum: 34: 1-3.2. van der Paardt M et al., (2005). No evidence for involvement of the Toll-like receptor 4 (TLR4) A896G and CD14-C260T polymorphisms in susceptibility to ankylosing spondylitis. Ann Rheum Dis: 64: 235-238.3. O'Connell JR and Weeks DE, (1998). PedCheck: A program for identifying genotype incompatibilities in linkage analysis. Am J Hum Genet: 63: 259-266.4. Clayton D, (1999). A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet: 65: 1170-177.Citation: Ann Rheum Dis, volume 66, supplement II, year 2007, page 136Session: Genomics, genetic basis of disease and HLA/T cell recognition