Date: Sunday, November 5, 2017
Session Title: Pediatric Rheumatology – Pathogenesis and Genetics
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Systemic juvenile idiopathic arthritis (sJIA) is a childhood inflammatory disease whose pathophysiology is poorly understood. sJIA is phenotypically heterogeneous with variable manifestations and responses to treatment. Until recently genetic investigations of sJIA have consisted of candidate gene studies in small patient collections. These studies found only modest associations, yet these associations are regularly included in discussions of sJIA pathophysiology. Therefore, we examined the 11 reported sJIA candidate susceptibility loci (IL1A/B, GLI2, IL1RN/PSD4, IL1R2, IL10/20, IL6, MVK, CCR5, MIF, SLC26A2 and TAPBP) in the largest sJIA study population assembled to date.
Methods: Single nucleotide polymorphism (SNP) genotypes were extracted from the INCHARGE dataset, (771 sJIA, 6947 controls). Logistic regression was performed in each case-control stratum and association results were meta-analyzed. The effect of sJIA associated SNPs on gene expression was evaluated in silico in paired whole genome (WGS) and RNA sequencing (RNAseq) data from lymphoblastoid cell lines (LCL) of 373 European 1000 Genomes Project subjects. The relationship between sJIA associated SNPs and response to recombinant interleukin-1 (IL-1) receptor antagonist (anakinra) treatment was evaluated in 38 US patients for whom treatment response data were available.
Results: None of the 26 SNPs with previously reported sJIA associations demonstrated even nominal (p<0.05) association with sJIA in our study. We expanded the analysis to determine whether the 11 loci containing the 26 SNPs harbored any sJIA risk SNPs. We examined 5479 SNPs from the 11 candidate regions, among which 500 SNPs were independent (r2<0.5), defining the study’s significance threshold as p<1E-4. Association meta-analysis revealed only one significant association among the 11 candidate loci, the promoter region of IL1RN, where 3 SNPs in strong linkage disequilibrium showed a significant association with sJIA. Analysis of LCL data showed that the sJIA associated SNPs correlated with IL1RN expression, with an inverse correlation between sJIA risk and IL1RN expression. Importantly, the presence of homozygous IL1RN high expression alleles correlated strongly with non-response to anakinra (p=9.8E-4, OR 17.3 [2.8, 108.1]).
Conclusion: IL1RN was the only candidate locus associated with sJIA in our study. The sJIA associated SNPs are among the strongest known determinants of IL1RN and IL1RA levels, linking low expression with increased sJIA risk. Although high expression alleles were protective against sJIA, patients with 2 high expression alleles were significantly less likely to respond to anakinra treatment than those with 1 or 2 low expression alleles. Even though anakinra is well known to ameliorate or reduce inflammation in some sJIA patients, this is the first report to link sJIA risk and response to anakinra treatment with genetically determined capacity to produce IL1RN or IL1RA. These SNPs are the first potential biomarker(s) capable of prospectively guiding therapeutic decision making in sJIA.
To cite this abstract in AMA style:Shuldiner E, Arthur V, Hinks A, Woo P, Thomson W, Remmers EF, Ombrello MJ. IL1RN Variation Is Associated with Systemic Juvenile Idiopathic Arthritis and Predicts Non-Response to Anakinra Treatment [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/il1rn-variation-is-associated-with-systemic-juvenile-idiopathic-arthritis-and-predicts-non-response-to-anakinra-treatment/. Accessed January 16, 2022.
« Back to 2017 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/il1rn-variation-is-associated-with-systemic-juvenile-idiopathic-arthritis-and-predicts-non-response-to-anakinra-treatment/