IL1RN Variation Influences both Disease Susceptibility and Response to Human Recombinant IL-1RA Therapy in Systemic Juvenile Idiopathic Arthritis

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (sJIA) susceptibility loci identified by candidate gene studies demonstrated association with sJIA in the largest study population assembled to date. METHODS: Single nucleotide polymorphisms ( SNPs) from 11 previously reported sJIA risk loci were examined for association in 9 populations, including 770 sJIA cases and 6947 control subjects. The effect of sJIA-associated SNPson gene expression was evaluated in silico in paired whole genome and RNA sequencing data from lymphoblastoid cell lines (LCL) of 373 European 1000 Genomes Projectsubjects. The relationship between sJIA-associated SNPsand response to anakinratreatment was evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association of the 26 SNPspreviously reported as sJIA-associated. Expanded analysis of the regions containing the 26 SNPsrevealed only one significant association, the promoter region of IL1RN (p<1E-4). sJIA-associated SNPscorrelated with IL1RN expression in LCLs, with an inverse correlation between sJIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with non-response to anakinratherapy (OR 28.7 [3.2, 255.8]). CONCLUSION: IL1RN was the only candidate locus associated with sJIA in our study. The implicated SNPsare among the strongest known determinants of IL1RN and IL1RA levels, linking low expression with increased sJIA risk. Homozygous high expression alleles predicted non-response to anakinratherapy, nominating them as candidate biomarkers to guide sJIA treatment. This is an important first step towards the personalized treatment of sJIA. This article is protected by copyright. All rights reserved.