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Background  To investigate the autoinflammatory hereditary periodic fever syndrome genes  MVK  and  TNFRSF1A,  and the  NLRP1  and  IL1  genes, for association with juvenile idiopathic arthritis (JIA).    Methods  For  MVK, TNFRSF1A  and  NLRP1  pair-wise tagging SNPs across each gene were selected and for  IL1A  SNPs from a prior meta-analysis were included. 1054 UK Caucasian JIA patients were genotyped by Sequenom iPlex MassARRAY and allele and genotype frequencies compared with 5380 unrelated healthy UK Caucasian controls.    Results  Four SNPs were significantly associated with UK JIA: rs2071374 within intron 4 of  IL1A  (ptrend=0.006), rs2228576 3’ of  TNFRSF1A  (ptrend=0.009) and 2 SNPs, rs11836136 and rs7957619, within  MVK  (ptrend=0.006, ptrend=0.005 respectively). In all cases the association appeared to be driven by the systemic-onset JIA (SoJIA) subtype. Genotype data for the two  MVK  SNPs was available in a validation cohort of 814 JIA (oligoarticular and RF negative polyarticular) cases and 3058 controls from the US. Replication was not confirmed, however, further suggesting that this association is specific to SoJIA.    Conclusions  These findings extend the observations of the relevance of studying monogenic loci as candidates for complex diseases. We provide novel evidence of association of  MVK  and  TNFRSF1A  with UK JIA, specifically driven by association with SoJIA and further confirm that the  IL1A  SNP association with SoJIA is subtype specific. Replication is required in independent cohorts.

Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic arthritis