Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic arthritis

Anne Hinks,Wendy Thomson,Susan D Thompson,Rachelle P Donn,Carmel J Stock,Thomas G Day,Marc Sudman,Paul Martin,Jon Packham,Athimalaipet V Ramanan

doi:10.1186/1546-0096-11-14

Abstract

BackgroundTo investigate the autoinflammatory hereditary periodic fever syndrome genes MVK and TNFRSF1A, and the NLRP1 and IL1 genes, for association with juvenile idiopathic arthritis (JIA).MethodsFor 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.ResultsFour 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.ConclusionsThese 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.

Highlights

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)
One single-nucleotide polymorphisms (SNPs), rs2071374 in the IL1 ligand cluster showed significant association with JIA (Table 1)
The association was with systemic-onset JIA (SoJIA) (p=0.001 odds ratios (ORs) 1.5 95% confidence intervals (CIs) 1.16-1.92)

Summary

Introduction

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). Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood. It occurs, by definition, before the age of 16 years, with a duration of more than six weeks. We have previously described associations between the psoriatic subtype of JIA and single-nucleotide polymorphisms (SNPs) in four genes responsible for monogenic hereditary periodic fever syndromes (HPFs) or autoinflammatory syndromes [7]. Arthralgia or arthritis is often part of the presenting form [8] They are caused by aberrant activation of the innate immune system, a mechanism that may be relevant to JIA

Methods

Results

Discussion

Conclusion