ASSOCIATION OF FAM167A(C8ORF13)-BLK AND TNFSF4 GENE VARIANTS WITH PRIMARY SJÖGREN'S SYNDROME

Background: Genetic factors contribute to the etiology of primary Sjögren's syndrome (pSS). Associations between pSS and genes outside the HLA-region have been investigated where polymorphisms in IRF5 and STAT4 have been convincingly associated and replicated as risk factors for pSS (1-3). Objectives: The aim of this study was to identify SNPs in candidate genes with a putative role in the immune pathogenesis of pSS. We included genes in the type I IFN system, genes involved in the inflammatory process in the minor salivary glands and lymphoma development and genes identified in genome wide association studies in SLE. Methods: A total of 1121 single nucleotide polymorphisms (SNPs) in 82 genes were included. Genotyping was performed using 250 ng DNA extracted from peripheral blood samples of the study subjects, by the Illumina GoldenGate assay. The study consisted of two cohorts, 344 pSS patients and 319 controls from Sweden and 196 pSS patients and 213 controls from Norway. Allele frequencies in cases and controls were compared using Fisher's exact test and a meta-analysis of the two cohorts was calculated with Cochran-Mantel Haenszel test, using the PLINK software Results: We found high signals for association between pSS and SNPs in several gene loci not previously associated with primary SS. Among these are the FAM167A(C8orf13)-BLK locus, P = 4.7 x 10, OR 1.37 and the TNFSF4 (Ox40L) gene, p = 7.4 x 10, OR 1.34, in the combined analysis of the Swedish and Norwegian cohorts. We also confirmed the association between pSS and the IRF5/TNPO3 locus, p = 5.5 x 10, OR 1.70, and the STAT4 gene, p = 7.0 x 10, OR 1.40. In addition, we found suggestive association signals with p-values < 0.01 in the combined cohort, from SNPs in five genes; the ICA1, CD14, BCL2, NFKB1 and C4A genes. There was no association between these SNPs and the presence of anti-SSA/anti-SSB antibodies. Conclusion: Both BLK and TNFSF4 are involved in B cell differentiation and activation and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS. References: 1. Korman BD, Alba MI, Le JM, Alevizos I, Smith JA, Nikolov NP et al. Variant form of STAT4 is associated with primary Sjögren's syndrome. Genes Immun 2008; 9: 267-270. 2. Miceli-Richard C, Comets E, Loiseau P, Puechal X, Hachulla E, Mariette X. Association of an IRF5 gene functional polymorphism with Sjögren's syndrome. Arthritis Rheum 2007; 56: 3989-3994. 3. Nordmark G, Kristjansdottir G, Theander E, Eriksson P, Brun JG, Wang C et al. Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome. Genes Immun 2009; 10: 68-76. Disclosure of Interest: None declaredCitation: Annals of the Rheumatic Diseases, volume 69, supplement 3, year 2010, page 345Session: SLE, Sjögren's and APS – etiology, pathogenesis and animal models (Poster Presentations )