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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Victoria L Arthur - , National Institutes of Health (NIH) (Author)
  • Emily Shuldiner - , National Institutes of Health (NIH) (Author)
  • Elaine F. Remmers - , National Institutes of Health (NIH) (Author)
  • Anne Hinks - , University of Manchester (Author)
  • Alexei A. Grom - , University of Cincinnati, Cincinnati Children's Hospital Medical Center (Author)
  • Dirk Foell - , University Hospital Münster (Author)
  • Alberto Martini - , IRCCS Istituto Giannina Gaslini - Genova, University of Genoa (Author)
  • Marco Gattorno - , IRCCS Istituto Giannina Gaslini - Genova, University of Genoa (Author)
  • Seza Özen - , Hacettepe University (Author)
  • Sampath Prahalad - , Emory University, Children's Healthcare of Atlanta (Author)
  • Andrew S. Zeft - , Cleveland Clinic Ohio (Author)
  • John F. Bohnsack - , University of Utah (Author)
  • Norman T Ilowite - , Albert Einstein College of Medicine, Children's Hospital at Montefiore (Author)
  • Elizabeth D. Mellins - , Stanford University (Author)
  • Ricardo A. G. Russo - , Hospital de Pediatría Prof. Dr. Juan P. Garrahan (Author)
  • Claudio Arnaldo Len - , Federal University of São Paulo (Author)
  • Sheila Knupp Oliveira - , Universidade Federal do Rio de Janeiro (Author)
  • Rae S. M. Yeung - , University of Toronto (Author)
  • Alan M. Rosenberg - , University of Saskatchewan (Author)
  • Lucy R. Wedderburn - , University College London (Author)
  • Jordi Antón - , University of Barcelona (Author)
  • Johannes Peter Haas - , German Center for Pediatric and Adolescent Rheumatology (Author)
  • Angela Rösen‐Wolff - , Department of Paediatrics (Author)
  • Kirsten Minden - , Charité – Universitätsmedizin Berlin, German Rheumatism Research Centre Berlin (Author)
  • Ann Marie Szymanski - , National Institutes of Health (NIH) (Author)
  • Wendy Thomson - , University of Manchester (Author)
  • Daniel L. Kastner - , National Institutes of Health (NIH) (Author)
  • Patricia Woo - , University College London (Author)
  • Michael J. Ombrello - , National Institutes of Health (NIH) (Author)

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.

Details

Original languageEnglish
Pages (from-to)1319-1330
JournalArthritis and Rheumatology
Volume70
Issue number8
Publication statusPublished - 28 Jun 2018
Peer-reviewedYes

External IDs

Scopus 85050600444

Keywords

Sustainable Development Goals

Keywords

  • Systemic juvenile idiopathic arthritis, genetics, IL1RN, anakinra, biomarker, personalized medicine