Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic Arthritis: Association with an exonic single nucleotide polymorphism in mevalonate kinase

Abstract

BACKGROUND: Autoinflammatory syndromes, also called hereditary periodic fever syndromes, are a heterogeneous group of diseases, unified by a common feature of cyclical episodes of unexplained inflammation and fever. Autoinflammatory syndromes have several overlapping features with JIA, especially with systemiconset JIA. We have previously studied SNPs in 4 genes that cause autoinflammatory diseases (NLRP3, NOD2, MEFV, and PSTPIP1) and shown association with psoriatic onset JIA (Day TG et al. 2008, Arth & Rheum, 58(7), 2142-6). Here we have studied SNPs across MVK, located on chromosome 12q24, responsible for hyper-IgD syndrome (H1DS), and TNFRSF1A, located on chromosome 12p13.2, responsible for TNF receptor-associated periodic syndrome (TRAPS). In addition, we studied SNPs across NALP1, a homologue of the autoinflammatory gene NALP3. SNPs in NALP1 have recently been associated with vitiligo-associated autoimmune disease, autoimmune Addison's disease, and type 1 diabetes. METHODS: DNA was available for 1054 UK Caucasian JIA patients. Pair-wise tagging SNPs were selected within 10kb up and down stream of each gene using an r2 cutoff (greater-than or equal to) 0.8 and MAF (greater-than or equal to) 0.05. SNP genotyping was performed using the Sequenom iPlex(registered trademark) MassARRAY platform according to manufacturers instructions. A 90% sample quality control rate and 90% SNP genotyping success rate was imposed on the analysis. Control samples genotype data was available from the Wellcome Trust case control consortium 2 (WTCCC2) (n=5380). Genotype and allele frequencies were compared between cases with JIA and controls using the Cochrane-Armitage trend test implemented in PLINK and allelic odds ratios (ORs) and their 95% confidence intervals (CIs) calculated. RESULTS: This study had >80% to detect an odds ratio >1.25 for SNPs with allele frequencies >0.1. Two SNPs in the MVK gene, rs1183616 (ptrend=0.006 OR 1.17 95% CI 1.04-1.30) and rs7957619 (ptrend=0.005 OR 1.23 95% CI 1.07-1.43) are significantly associated with JIA. These two SNPs are in modest linkage disequilibrium (r2=0.36, D'=1). Logistic regression of the two SNPs, after conditioning on the most significant SNP, found that the rsll83616 SNP was no longer significant (p=0.3), suggesting that the association is a single effect driven by the rs7957619 SNP. This SNP lies within exon 3 of the MVK gene and is a Serine to Asparagine substitution at position 52. There was no significant evidence of a difference in allele frequencies between the seven ILAR subtypes for the rs7957619 SNP (p=0.32). One SNP at the 3' end of the TNFRSF1A gene, which actually lies within the adjacent gene SLCNNIA, rs2228576, was associated with protection from JIA (ptrend=0.009 OR 0.87 95% CI 0.78-0.97). There was no significant evidence of a difference in allele frequencies between the seven ILAR subtypes (p=0.94). None of the 16 SNPs studied across the NALPI gene were found to be associated with JIA susceptibility. DISCUSSION: We have utilised the largest cohort of JIA cases available in Europe and identified associations between JIA and polymorphisms 3' of TNFRSF1 and within MVK. Replication of these findings in other JIA populations is required. These observations support the value of extrapolating from monogenic to complex disease phenotypes.