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Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic arthritis

Anne Hinks1, Paul Martin1, Susan D Thompson2, Marc Sudman2, Carmel J Stock3, Wendy Thomson1, Thomas G Day1, Jon Packham4, Childhood arthritis prospective study (CAPS), BSPAR study group, Athimalaipet V Ramanan5 and Rachelle P Donn1*

Author Affiliations

1 Arthritis Research UK Epidemiology Unit, Stopford Building, The University of Manchester, Manchester Academic Health Science Centre, School of Translational Medicine, Oxford Road, Manchester M13 9PT, UK

2 Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA

3 Centre for Paediatric and Adolescent Rheumatology, Windeyer Institute for Medical Sciences, University College London, London, UK

4 Haywood Hospital, University Hospital of North Staffordshire, Stoke on Trent, Staffordshire ST4 7LN, UK

5 Department of Paediatric Rheumatology, Bristol Royal Hospital for Children & Royal National Hospital for Rheumatic Diseases, Bath, UK

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Pediatric Rheumatology 2013, 11:14  doi:10.1186/1546-0096-11-14

Published: 2 April 2013



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).


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.


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.


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 genes; Juvenile idiopathic arthritis; MVK; TNFRSF1A; IL1A