ASSOCIATION OF STAT4 VARIANTS AND ANKYLOSING SPONDYLITIS (AS)

R.D. Inman, W.P. Maksymowych, D.D. Gladman, J. Reeve, L. Peddle, M. Uddin, P. RahmanRheumatology, University of Toronto, Toronto; Rheumatology, University of Alberta, Edmonton; Rheumatology, Memorial University of Newfoundland, St. Johns, CanadaObjectives: A variant of a STAT4 has been recently shown to confer increased risk for both RA and SLE (Remmers EF et al; NEJM 2007). STAT4 encodes a transcription factor that transmits signals induced by type 1 interferons, IL-12 and IL-23. There is evidence of IFN-γ dysregulation in macrophages derived from AS patients. In addition. the association between IL23R and AS has now been established, Thus STAT4 may play an important role in susceptibility to AS. In this study, the association of STAT4 variants in three well defined Canadian AS cohorts was examined.Methods: In total there were 888 AS cases and 927 controls, comprised from three AS centers in Canada (472 cases and 451 controls from Alberta (AL); 278 cases and 114 controls from Toronto (TO), 138 cases and 392 controls from the Newfoundland founder population (NL). The majority of AS patients were Caucasians of North European descent and satisfied the modified New York Classification Criteria. All samples were genotyped for a panel of 4 SNPs (rs11889341, rs7574865, rs8179673, rs10181656) using the Sequenom MassARRAY technology. As there was strong LD across all markers, SNP rs7574865 was used for the association study, as this particular variant was reported in previous RA and SLE studies.Results: The minor allele frequency for the (T) allele for SNP rs7574865 was 0.218 in AS cases and 0.258 in controls from AL; 0.209 in AS cases and 0.274 in controls from TO; and 0.208 in AS cases and 0.215 in controls from NL. There was a marginal association when all AS cases were combined and compared to all controls (p=0.040; see Table 1). However, there was significant heterogeneity between the NL controls and the other two control populations (AL+TO). Also the minor allele frequency for rs7574865 in NL was different than that reported in public databases and in the previous studies in RA and SLE. Consequently, when data from AL and TO populations was combined there was a significant association between SNP rs7574865 and AS.(p=0.006; see Table 1). Population SNP Minor Allele Case Freq Control Freq OR 95% CI P-Value AL + TO + NL rs7574865 (T) 0.214 0.243 0.84 0.72-0.99 0.040 AL + TO rs7574865 (T) 0.215 0.261 0.77 0.64-0.93 0.006 Conclusion: The same STAT4 variant associated with RA and SLE is also significantly associated with admixed Caucasian AS population from Canada. Molecular mechanisms of STAT4 in AS needs to be investigated in order to shed new light into the pathogenesis of AS.References: Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosusCitation: Ann Rheum Dis, volume 67, supplement II, year 2008, page 514Session: Spondylarthropathies