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

INCHARGE Consortium

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1319-1330
Number of pages12
JournalArthritis and Rheumatology
Volume70
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Interleukin-1 Receptors
Juvenile Arthritis
Disease Susceptibility
Single Nucleotide Polymorphism
Interleukin 1 Receptor Antagonist Protein
Therapeutics
Alleles
Genome
RNA Sequence Analysis
Cell Line
Genetic Association Studies
Genetic Promoter Regions
Computer Simulation
Population
Biomarkers
Odds Ratio
Confidence Intervals
Gene Expression

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

@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 Todd} 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.}",
year = "2018",
month = "8",
day = "1",
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",

}

TY - JOUR

T1 - IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis

AU - INCHARGE Consortium

AU - Arthur, Victoria L.

AU - Shuldiner, Emily

AU - Remmers, Elaine F.

AU - Hinks, Anne

AU - Grom, Alexei A.

AU - Foell, Dirk

AU - Martini, Alberto

AU - Gattorno, Marco

AU - Özen, Seza

AU - Prahalad, Sampath

AU - Zeft, Andrew S.

AU - Bohnsack, John F.

AU - Ilowite, Norman Todd

AU - Mellins, Elizabeth D.

AU - Russo, Ricardo

AU - Len, Claudio

AU - Oliveira, Sheila

AU - Yeung, Rae S.M.

AU - Rosenberg, Alan M.

AU - Wedderburn, Lucy R.

AU - Anton, Jordi

AU - Haas, Johannes Peter

AU - Rösen-Wolff, Angela

AU - Minden, Kirsten

AU - Szymanski, Ann Marie

AU - Thomson, Wendy

AU - Kastner, Daniel L.

AU - Woo, Patricia

AU - Ombrello, Michael J.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85050600444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050600444&partnerID=8YFLogxK

U2 - 10.1002/art.40498

DO - 10.1002/art.40498

M3 - Article

C2 - 29609200

AN - SCOPUS:85050600444

VL - 70

SP - 1319

EP - 1330

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 8

ER -