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

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 70; no. 8; pp. 1319 - 1330
• Main Authors: Arthur, Victoria L., Grom, Alexei A., Foell, Dirk, Özen, Seza, Prahalad, Sampath, Mellins, Elizabeth D., Russo, Ricardo, Oliveira, Sheila, Yeung, Rae S. M., Rosenberg, Alan M., Minden, Kirsten, Kastner, Daniel L., Woo, Patricia, Ombrello, Michael J., Docampo, Elisa, Estivill, Xavier, Gattorno, Marco, Grom, Alexei, Gül, Ahmet, Haas, Johannes‐Peter, Kottyan, Leah C., Langefeld, Carl D., Martini, Alberto, Pinto, Dalila, Rosenberg, Alan, Scherer, Stephen W., Signa, Sara, Shuldiner, Emily, Tachmazidou, Ioanna, Thompson, Susan, Thomson, Wendy, Wedderburn, Lucy R., Zeggini, Eleftheria, Chédeville, Gaëlle, Chetaille, Anne‐Laure, Dancey, Paul, Ellsworth, Janet, Guzman, Jaime, Jurencak, Roman, Schneider, Rayfel, Spiegel, Lynn, Stringer, Elizabeth, Tucker, Lori B., Wintle, Richard F., Abinum, Mario, Bell, A., Hall, M., Hollingworth, Peter, Stewart, I., Baildam, Eileen, Bishop, Nick, Brown, Lynsey, Davidson, Joyce, Friel, Elizabeth, Hadfield, Kelly, Lay, Mark, Lloyd, Olivia, Lydon, Carol, Makengo, Natasha, Moorcroft, Theresa, Price, Vicki, Venter, Katharine, Zelenovic, Jadranka, Foeldvari, Ivan, Heiligenhaus, Arnd, Kallinich, Tilmann, Kümmerle‐Deschner, Jasmin, Mönkemöller, Kirsten, Elder, Melissa, Gottlieb, Beth S., Imundo, Lisa F., Miller, Michael L., Prather, Kristi, Singer, Nora G., Spalding, Steven J., Tarvin, Stacey E., Verbsky, James W., Wallace, Carol A., Cutts, Rebecca, Etheridge, Angela, Hinks, Anne, Howman, Ruth, Marshall, Lucy, Melville, Laura, Moncrieffe, Halima, Mulligan, Kathleen, Palman, Jason, Robinson, Emily, Simou, Stephanie, Stafford, Stefanie, Southwood, Tauny
• Format: Journal Article Web Resource
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2018; John Wiley & Sons
• Subjects: Alleles; Antirheumatic Agents - pharmacology; Arthritis; Arthritis, Juvenile - drug therapy; Arthritis, Juvenile - genetics; Biomarkers; Case-Control Studies; Child; Confidence intervals; Correlation; Cytokines; Female; Gene expression; Gene sequencing; Genetic Predisposition to Disease - genetics; Genetics & genetic processes; Genome-Wide Association Study; Genomes; Génétique & processus génétiques; Human behavior; Humans; Interleukin 1; Interleukin 1 receptor antagonist; Interleukin 1 Receptor Antagonist Protein - drug effects; Interleukin 1 Receptor Antagonist Protein - genetics; Interleukin 1 Receptor Antagonist Protein - pharmacology; Interleukins; Life sciences; Loci; Lymphoblastoid cell lines; Male; Odds Ratio; Patients; Pharmacogenomic Variants - drug effects; Pharmacogenomic Variants - genetics; Polymorphism, Single Nucleotide - drug effects; Polymorphism, Single Nucleotide - genetics; Population studies; Promoter Regions, Genetic - genetics; Ribonucleic acid; Risk; RNA; Sciences du vivant; Single-nucleotide polymorphism; Therapy
• ISSN: 2326-5191; 2326-5205; 2326-5205
• DOI: 10.1002/art.40498

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.