@article{67a1b26411eb45299289f5359121c1c3,
title = "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.",
author = "{INCHARGE Consortium} and Arthur, {Victoria L.} and Emily Shuldiner and Remmers, {Elaine F.} and Anne Hinks and Grom, {Alexei A.} and Dirk Foell and Alberto Martini and Marco Gattorno and Seza {\"O}zen and Sampath Prahalad and Zeft, {Andrew S.} and Bohnsack, {John F.} and Ilowite, {Norman T.} and Mellins, {Elizabeth D.} and Ricardo Russo and Claudio Len and Sheila Oliveira and Yeung, {Rae S.M.} and Rosenberg, {Alan M.} and Wedderburn, {Lucy R.} and Jordi Anton and Haas, {Johannes Peter} and Angela R{\"o}sen-Wolff and Kirsten Minden and Szymanski, {Ann Marie} and Wendy Thomson and Kastner, {Daniel L.} and Patricia Woo and Ombrello, {Michael J.}",
note = "Funding Information: The CAPS study was funded by Arthritis Research UK (20542). SPARKS-CHARMS was funded by grants from SPARKS UK (08ICH09 and 12ICH08) and the Medical Research Council (MR/M004600/1), and supported by the NIHR Biomedical Research Centres at Great Ormond Street Hospital for Children National Health Service Foundation Trust and University College London Hospitals Trust, and the NIHR-Clinical Research Network. The BBOP study was supported by the Canadian Institutes of Health Research (CIHR) and the Arthritis Society (CIHR funding reference number 82517) and the Canadian Arthritis Network (funding reference SRI-IJD-01). This research was supported in part by the Cincinnati Children{\textquoteright}s Research Foundation and its Cincinnati Genomic Control Cohort. The authors acknowledge the use of DNA from the UK Blood Services collection of Common Controls (funded by Wellcome Trust grant 076113/C/04/Z and by the US NIH research program grant to the National Health Service Blood and Transplant [RP-PG-0310-1002]) and from the British 1958 Birth Cohort collection (funded by the UK Medical Research Council grant G0000934 and by Wellcome Trust grant 068545/Z/02). This work utilized the computational resources of the NIH High Performance Computing Biowulf cluster (http://hpc.nih.gov). Funding Information: The CAPS study was funded by Arthritis Research UK (20542). SPARKS-CHARMS was funded by grants from SPARKS UK (08ICH09 and 12ICH08) and the Medical Research Council (MR/M004600/1), and supported by the NIHR Biomedical Research Centres at Great Ormond Street Hospital for Children National Health Service Foundation Trust and University College London Hospitals Trust, and the NIHR-Clinical Research Network. The BBOP study was supported by the Canadian Institutes of Health Research (CIHR) and the Arthritis Society (CIHR funding reference number 82517) and the Canadian Arthritis Network (funding reference SRI-IJD-01). This research was supported in part by the Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort. The authors acknowledge the use of DNA from the UK Blood Services collection of Common Controls (funded by Wellcome Trust grant 076113/C/04/Z and by the US NIH research program grant to the National Health Service Blood and Transplant [RP-PG-0310-1002]) and from the British 1958 Birth Cohort collection (funded by the UK Medical Research Council grant G0000934 and by Wellcome Trust grant 068545/Z/02). This work utilized the computational resources of the NIH High Performance Computing Biowulf cluster (http://hpc.nih.gov). Funding Information: Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Programs grant Z01-AR-041198 [to Dr. Ombrello] and National Human Genome Research Institute grant Z01-HG-200370 [to Dr. Kastner]). Additional support was provided by NIH grants R01-AR-059049 (to Dr. Grom), R01-AR-061297 (to Dr. Mellins), and R01-AR-060893 (to Dr. Prahalad), Arthritis Research UK (grant 20385 to Dr. Thomson), the German Federal Ministry of Education and Research (BMBF project grants 01ER0813 and 01ER0812 [to Drs. Minden and Foell] and 01ER0828 [to Dr. Minden]), the Val A. Browning Charitable Foundation (grant to Dr. Bohnsack), and the Marcus Foundation (grant to Dr. Prahalad). Drs. Thomson and Hinks{\textquoteright} work was supported by the Manchester Academic Health Sciences Centre and the NIHR Biomedical Research Unit Funding Scheme. Dr. Wedderburn{\textquoteright}s work was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. Publisher Copyright: {\textcopyright} 2018, American College of Rheumatology",
year = "2018",
month = aug,
doi = "10.1002/art.40498",
language = "English (US)",
volume = "70",
pages = "1319--1330",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "8",
}
