IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis

Abstract

Objective: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date.

Methods: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available.

Results: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10^-4 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]).

Conclusion: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

Figure 1. INCHARGE sJIA case-control regional association plots of loci previously implicated by candidate gene studies

Regional association plots for previously reported sJIA candidate susceptibility loci near IL1A/B (A), GLI2 (B), IL1RN/PSD4 (C), IL1R2 (D), IL10/20 (E), IL6 (F), MVK (G), CCR5 (H), MIF (I), SLC26A2 (J), and TAPBP (K) show minimal significance in INCHARGE case-control dataset, except for a cluster of SNPs in the IL1RN/PSD4 region (C). None of the top SNPs from previous candidate studies (labeled and denoted by red diamonds) showed even nominal significance with sJIA. Other SNPs in the candidate loci are shown as blue circles. The brown horizontal line demonstrates the study-wide significance threshold.

Figure 2. Variants of the IL1RN locus are associated with sJIA in the INCHARGE case-control collection

SNP associations within the IL1RN locus are shown, colored by pairwise linkage disequilibrium (LD) with the most strongly associated SNP, rs55663133 (A). The brown horizontal line demonstrates the study-wide significance threshold. In Panel B, a forest plot demonstrates the effect size of rs55663133 by meta-analysis and in individual study populations. Panel C displays pairwise LD with the peak sJIA-associated SNP, rs55663133 (star) in the U.S. case-control population. The top 7 sJIA associated markers (19–25) form a strong LD block.

Figure 3. Relationship of IL1RN expression and IL-1RA protein levels with sJIA-associated SNPs

IL1RN expression by RNA sequencing from the study of Lappalainen et al. is shown, stratified by genotype, for representative sJIA-associated SNPs (A and B). Dot plots depict all SNPs with reported correlations with IL1RN expression (C and D) or IL-1RA protein levels (E) in the studies by Westra et al. , Lappalainen et al. , and Herder et al. , respectively. SNPs among the top 42 sJIA-associated SNPs are highlighted in green (sJIA protective alleles) and gold (sJIA risk alleles), and the top 7 sJIA-associated SNPs are highlighted in red.