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Rheumatology"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single\u2010nucleotide 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\u2013associated 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\u2013associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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 <jats:italic>IL1RN<\/jats:italic> (<jats:italic>P<\/jats:italic> &lt; 1 \u00d7 10<jats:sup>\u20134<\/jats:sup>). Systemic JIA\u2013associated SNPs correlated with <jats:italic>IL1RN<\/jats:italic> expression in LCLs, with an inverse correlation between systemic JIA risk and <jats:italic>IL1RN<\/jats:italic> expression. The presence of homozygous <jats:italic>IL1RN<\/jats:italic> high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2\u2013255.8]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In our study, <jats:italic>IL1RN<\/jats:italic> was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of <jats:italic>IL1RN<\/jats:italic> and interleukin\u20101 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40498","type":"journal-article","created":{"date-parts":[[2018,4,2]],"date-time":"2018-04-02T18:55:21Z","timestamp":1522695321000},"page":"1319-1330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["<i>IL1RN<\/i> Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin\u20101 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"Victoria L.","family":"Arthur","sequence":"first","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Shuldiner","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine F.","family":"Remmers","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute NIH Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Hinks","sequence":"additional","affiliation":[{"name":"Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei A.","family":"Grom","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Foell","sequence":"additional","affiliation":[{"name":"University Hospital M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Martini","sequence":"additional","affiliation":[{"name":"G. 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