IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin‐1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis. Issue 8 (28th June 2018)

• Record Type: Journal Article
• Authors: Arthur, Victoria L.; Shuldiner, Emily; Remmers, Elaine F.; Hinks, Anne; Grom, Alexei A.; Foell, Dirk; Martini, Alberto; Gattorno, Marco; Özen, Seza; Prahalad, Sampath; Zeft, Andrew S.; Bohnsack, John F.; Ilowite, Norman T.; Mellins, Elizabeth D.; Russo, Ricardo; Len, Claudio; Oliveira, Sheila; Yeung, Rae S. M.; Rosenberg, Alan M.; Wedderburn, Lucy R.; Anton, Jordi; Haas, Johannes‐Peter; Rösen‐Wolff, Angela; Minden, Kirsten; Szymanski, Ann Marie; Thomson, Wendy; Kastner, Daniel L.; Woo, Patricia; Ombrello, Michael J.
• Other Names: Achkar Jean‐Paul investigator.; Alarcón‐Riquelme Marta E. investigator.; Anton Jordi investigator.; Arthur Victoria L. investigator.; Baskin Elizabeth investigator.; Bohnsack John F. investigator.; Cobb Joanna investigator.; Demirkaya Erkan investigator.; Docampo Elisa investigator.; Duerr Richard H. investigator.; Estivill Xavier investigator.; Foell Dirk investigator.; Gattorno Marco investigator.; Grom Alexei investigator.; Gül Ahmet investigator.; Hilario Maria Odete E. investigator.; Ilowite Norman T. investigator.; Haas Johannes‐Peter investigator.; Hinks Anne investigator.; Ilyas Kamboh M. investigator.; Kastner Daniel L. investigator.; Kaufman Kenneth M. investigator.; Kottyan Leah C. investigator.; Langefeld Carl D. investigator.; Len Claudio investigator.; Martini Alberto investigator.; Mellins Elizabeth D. investigator.; Minden Kirsten investigator.; Oliveira Sheila investigator.; Ombrello Michael J. investigator.; Özen Seza investigator.; Pinto Dalila investigator.; Prahalad Sampath investigator.; Remmers Elaine F. investigator.; Rosen‐Wolff Angela investigator.; Rosenberg Alan investigator.; Russo Ricardo investigator.; Scherer Stephen W. investigator.; Signa Sara investigator.; Shuldiner Emily investigator.; Szymanski Ann Marie investigator.; Tachmazidou Ioanna investigator.; Tenbrock Klaus investigator.; Thompson Susan investigator.; Thomson Wendy investigator.; Wedderburn Lucy R. investigator.; Woo Patricia investigator.; Yeung Rae S. M. investigator.; Zeft Andrew S. investigator.; Zeggini Eleftheria investigator.; Baxter‐Jones Adam investigator.; Benseler Susanne investigator.; Boire Gilles investigator.; Cabral David A. investigator.; Cameron Bonnie investigator.; Campillo Sarah investigator.; Chédeville Gaëlle investigator.; Chetaille Anne‐Laure investigator.; Dancey Paul investigator.; Duffy Ciaran investigator.; Duffy Karen Watanabe investigator.; Ellsworth Janet investigator.; Gibbon Michele investigator.; Guillet Chantal investigator.; Guzman Jaime investigator.; Houghton Kristin investigator.; Huber Adam M. investigator.; Jurencak Roman investigator.; Lang Bianca investigator.; Laxer Ronald M. investigator.; Maenz Lynn investigator.; Matheson Loren investigator.; Oen Kiem G. investigator.; Petty Ross E. investigator.; Ramsey Suzanne E. investigator.; Rezaei Elham investigator.; Rosenberg Alan M. investigator.; Roth Johannes investigator.; Schneider Rayfel investigator.; Scuccimarri Rosie investigator.; Scherer Stephen W. investigator.; Silverman Earl investigator.; Spiegel Lynn investigator.; Stringer Elizabeth investigator.; Tse Shirley M. L. investigator.; Tucker Lori B. investigator.; Turvey Stuart investigator.; Wintle Richard F. investigator.; Yeung Rae S. M. investigator.; Abinum Mario investigator.; Bell A. investigator.; Craft Alan W. investigator.; Crawley Esther investigator.; David Joel investigator.; Foster Helen investigator.; Gardener‐Medwin Janet investigator.; Griffin Jane investigator.; Hall Ann investigator.; Hall M. investigator.; Herrick Ariane L. investigator.; Hollingworth Peter investigator.; Holt Lennox investigator.; Jones Stan investigator.; Pountain Gillian investigator.; Ryder Clive investigator.; Southwood Tauny investigator.; Stewart I. investigator.; Venning Helen investigator.; Wedderburn Lucy R. investigator.; Woo Patricia investigator.; Wyatt Sue investigator.; Baildam Eileen investigator.; Bishop Nick investigator.; Brown Lynsey investigator.; Buckley Joanne investigator.; Chieng Alice investigator.; Carrasco Roberto investigator.; Cobb Joanna investigator.; Cook Lucy investigator.; Davidson Joyce investigator.; Duggan Annette investigator.; Eltringham Michael investigator.; Foster Helen investigator.; Friel Elizabeth investigator.; Friswell Mark investigator.; Gardner‐Medwin Janet investigator.; Gilbert Paul investigator.; Gould Vikki investigator.; Hadfield Kelly investigator.; Hyrich Kimme investigator.; Jones Julie investigator.; Lal Sham investigator.; Lay Mark investigator.; Lloyd Gabrielle investigator.; Lloyd Olivia investigator.; Lydon Carol investigator.; Makengo Natasha investigator.; McGovern Ann investigator.; Meijer Alexandra investigator.; Mills‐Wierda Nicola investigator.; Moorcroft Theresa investigator.; Price Vicki investigator.; Qiao Liang investigator.; Riding Kay investigator.; Sim Jane investigator.; Southwood Tauny investigator.; Thomson Wendy investigator.; Todd Maureen investigator.; Tremble Susan investigator.; Venter Katharine investigator.; Wade Debbie investigator.; Ward Peter investigator.; Watson Sharon investigator.; Webster Gwen investigator.; Wedderburn Lucy R investigator.; Zelenovic Jadranka investigator.; Foeldvari Ivan investigator.; Foell Dirk investigator.; Ganser Gerd investigator.; Haas Johannes‐Peter investigator.; Heiligenhaus Arnd investigator.; Horneff Gerd investigator.; Hospach Anton investigator.; Huppertz Hans‐Iko investigator.; Kallinich Tilmann investigator.; Kümmerle‐Deschner Jasmin investigator.; Minden Kirsten investigator.; Mönkemöller Kirsten investigator.; Thon Angelika investigator.; Birmingham James D. investigator.; Elder Melissa investigator.; Gottlieb Beth S. investigator.; Ilowite Normal T. investigator.; Imundo Lisa F. investigator.; Kimura Yukiko investigator.; Lokhnygina Yuliya investigator.; Miller Michael L. investigator.; Milojevic Diana investigator.; O'Neil Kathleen investigator.; Punaro Marilynn G. investigator.; Prather Kristi investigator.; Ruth Natasha M. investigator.; Sandborg Christy I. investigator.; Schanberg Laura E. investigator.; Sherry David D. investigator.; Singer Nora G. investigator.; Spalding Steven J. investigator.; Tarvin Stacey E. investigator.; Verbsky James W. investigator.; Wallace Carol A. investigator.; Zemel Lawrence S. investigator.; Armon Kate investigator.; Burkle Katrin investigator.; Cobb Joanna investigator.; Cutts Rebecca investigator.; Etheridge Angela investigator.; Giannakopoulou Eirini investigator.; Gilbert Paul investigator.; Hinks Anne investigator.; Hirani Shashi investigator.; Heard Clare investigator.; Howman Ruth investigator.; Johnson Cerise investigator.; Kassoumeri Laura investigator.; Lal Sham investigator.; Leahy Alice investigator.; Marshall Lucy investigator.; Melville Laura investigator.; Moncrieffe Halima investigator.; Mulligan Kathleen investigator.; Newman Stanton investigator.; Palman Jason investigator.; Patrick Fiona investigator.; Robinson Emily investigator.; Simou Stephanie investigator.; Stafford Stefanie investigator.; Southwood Tauny investigator.; Thomson Wendy investigator.; Tucker Petra investigator.; Ursu Simona investigator.; Warrier Kishore investigator.; Watts Joanna investigator.; Wedderburn Lucy R. investigator.; Whitworth Pamela investigator.; Woo Patricia investigator.;
• Is Part Of: Arthritis & rheumatology. Volume 70:Issue 8(2018)
• Page Start: 1319
• Page End: 1330
• Publication Date: 2018-06-28
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.40498
• Languages: English
• ISSNs: 2326-5191

Abstract

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.