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

• Type of Material: Article
• Authors: Victoria L. Arthur, National Institutes of Health; Emily Shuldiner, National Institutes of Health; Elaine F. Remmers, National Institutes of Health; Anne Hinks, University of Manchester; Alexei A. Grom, University of Cincinnati; Dirk Foell, University Hospital Münster; Alberto Martini, G. Gaslini Institute; Marco Gattorno, University of Genoa; Seza Ozen, Hacettepe University; Sampath Prahalad, Emory University; Andrew S. Zeft, Cleveland Clinic; John F. Bohnsack, University of Utah; Norman T. Ilowite, Albert Einstein College of Medicine; Elizabeth D. Mellins, Stanford University; Ricardo Russo, Hospital de Pediatria Garrahan; Claudio Len, Universidade Federal de São Paulo; Sheila Oliveira, Universidade Federal de Rio de Janeiro; Rae S. M. Yeung, University of Toronto; Alan M. Rosenberg, University of Saskatchewan; Lucy R. Wedderburn, University College London; Jordi Anton, University of Barcelona; Johannes-Peter Haas, German Center for Pediatric and Adolescent Rheumatology; Angela Roesen-Wolff, University Hospital Cal Gustav Carus; Kirsten Minden, Charite University; Ann Marie Szymanski, National Institutes of Health; Wendy Thomson, University of Manchester; Daniel L. Kastner, National Institutes of Health; Patricia Woo, University College London; Michael J. Ombrello, National Institutes of Health
• Language: English
• Date: 2018-08-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, American College of Rheumatology
• Final Published Version (URL): http://dx.doi.org/10.1002/art.40498
• Title of Journal or Parent Work: Arthritis and Rheumatology
• ISSN: 2326-5191
• Volume: 70
• Issue: 8
• Start Page: 1319
• End Page: 1330
• Grant/Funding Information: LRW is supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre.; Additional support was provided by NIH grants R01-AR059049 (AAG), R01-AR061297 (EDM), and R01-AR060893 (SP); Arthritis Research UK Grant 20385 (WT); the German Federal Ministry of Education and Research (BMBF projects 01ER0813 and 01ER0812 to KM and DF, BMBF project 01ER0828 to KM); the Val A. Browning Charitable Foundation (JFB); and the Marcus Foundation (SP).; This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198 to MJO) and the National Human Genome Research Institute (Z01-HG200370 to DLK) of the National Institutes of Health (NIH).; WT and AH are supported by the Manchester Academic Health Sciences Centre (MAHSC) and are funded by the National Institute for Health Research (NIHR) Biomedical Research Unit Funding Scheme.
• Keywords: TRAITS; ACTIVATION; POLYMORPHISMS; GENE-EXPRESSION PROFILES; VARIANTS; PERIPHERAL-BLOOD; ASSOCIATION; Science & Technology; Rheumatology; FAMILY; CHILDREN; Life Sciences & Biomedicine
• Research Categories: Biology, Genetics

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.