☆ 4.5 Article

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

ARTHRITIS & RHEUMATOLOGY (2018)

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ARTHRITIS & RHEUMATOLOGY
卷 70, 期 8, 页码 1319-1330

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WILEY
DOI: 10.1002/art.40498

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Rheumatology

资金

  1. Arthritis Research UK [20542]
  2. SPARKSUK [08ICH09, 12ICH08]
  3. Medical Research Council [MR/M004600/1]
  4. NIHR Biomedical Research Centres at Great Ormond Street Hospital for Children National Health Service Foundation Trust
  5. University College London Hospitals Trust
  6. NIHR-Clinical Research Network
  7. Canadian Institutes of Health Research (CIHR)
  8. Arthritis Society (CIHR) [82517]
  9. Canadian Arthritis Network [SRI-IJD-01]
  10. Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort
  11. Wellcome Trust [076113/C/04/Z]
  12. US NIH [RP-PG-0310-1002]
  13. British 1958 Birth Cohort collection
  14. UK Medical Research Council [G0000934]
  15. Wellcome Trust grant [068545/Z/02]
  16. MRC [MR/R013926/1, MR/M004600/1] Funding Source: UKRI
  17. Great Ormond Street Hospital Childrens Charity [V1304] Funding Source: researchfish
  18. Medical Research Council [MR/R013926/1, MR/M004600/1] Funding Source: researchfish
  19. National Institute for Health Research [NF-SI-0616-10099] Funding Source: researchfish
  20. Versus Arthritis [20542] Funding Source: researchfish

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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 x 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.

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