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Arthritis Rheumatol. 2018 Aug;70(8):1319-1330. doi: 10.1002/art.40498. Epub 2018 Jun 28.

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

Collaborators (225)

Achkar JP, Alarcón-Riquelme ME, Anton J, Arthur VL, Baskin E, Bohnsack JF, Cobb J, Demirkaya E, Docampo E, Duerr RH, Estivill X, Foell D, Gattorno M, Grom A, Gül A, Hilario MOE, Ilowite NT, Haas JP, Hinks A, Ilyas Kamboh M, Kastner DL, Kaufman KM, Kottyan LC, Langefeld CD, Len C, Martini A, Mellins ED, Minden K, Oliveira S, Ombrello MJ, Özen S, Pinto D, Prahalad S, Remmers EF, Rosen-Wolff A, Rosenberg A, Russo R, Scherer SW, Signa S, Shuldiner E, Szymanski AM, Tachmazidou I, Tenbrock K, Thompson S, Thomson W, Wedderburn LR, Woo P, Yeung RSM, Zeft AS, Zeggini E, Baxter-Jones A, Benseler S, Boire G, Cabral DA, Cameron B, Campillo S, Chédeville G, Chetaille AL, Dancey P, Duffy C, Duffy KW, Ellsworth J, Gibbon M, Guillet C, Guzman J, Houghton K, Huber AM, Jurencak R, Lang B, Laxer RM, Maenz L, Matheson L, Oen KG, Petty RE, Ramsey SE, Rezaei E, Rosenberg AM, Roth J, Schneider R, Scuccimarri R, Scherer SW, Silverman E, Spiegel L, Stringer E, Tse SML, Tucker LB, Turvey S, Wintle RF, Yeung RSM, Abinum M, Bell A, Craft AW, Crawley E, David J, Foster H, Gardener-Medwin J, Griffin J, Hall A, Hall M, Herrick AL, Hollingworth P, Holt L, Jones S, Pountain G, Ryder C, Southwood T, Stewart I, Venning H, Wedderburn LR, Woo P, Wyatt S, Baildam E, Bishop N, Brown L, Buckley J, Chieng A, Carrasco R, Cobb J, Cook L, Davidson J, Duggan A, Eltringham M, Foster H, Friel E, Friswell M, Gardner-Medwin J, Gilbert P, Gould V, Hadfield K, Hyrich K, Jones J, Lal S, Lay M, Lloyd G, Lloyd O, Lydon C, Makengo N, McGovern A, Meijer A, Mills-Wierda N, Moorcroft T, Price V, Qiao L, Riding K, Sim J, Southwood T, Thomson W, Todd M, Tremble S, Venter K, Wade D, Ward P, Watson S, Webster G, Wedderburn LR, Zelenovic J, Foeldvari I, Foell D, Ganser G, Haas JP, Heiligenhaus A, Horneff G, Hospach A, Huppertz HI, Kallinich T, Kümmerle-Deschner J, Minden K, Mönkemöller K, Thon A, Birmingham JD, Elder M, Gottlieb BS, Ilowite NT, Imundo LF, Kimura Y, Lokhnygina Y, Miller ML, Milojevic D, O'Neil K, Punaro MG, Prather K, Ruth NM, Sandborg CI, Schanberg LE, Sherry DD, Singer NG, Spalding SJ, Tarvin SE, Verbsky JW, Wallace CA, Zemel LS, Armon K, Burkle K, Cobb J, Cutts R, Etheridge A, Giannakopoulou E, Gilbert P, Hinks A, Hirani S, Heard C, Howman R, Johnson C, Kassoumeri L, Lal S, Leahy A, Marshall L, Melville L, Moncrieffe H, Mulligan K, Newman S, Palman J, Patrick F, Robinson E, Simou S, Stafford S, Southwood T, Thomson W, Tucker P, Ursu S, Warrier K, Watts J, Wedderburn LR, Whitworth P, Woo P.

Author information

1
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
2
National Human Genome Research Institute, NIH, Bethesda, Maryland.
3
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.
4
University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
5
University Hospital Münster, Münster, Germany.
6
G. Gaslini Institute and University of Genoa, Genoa, Italy.
7
Hacettepe University, Ankara, Turkey.
8
Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
9
Cleveland Clinic, Cleveland, Ohio.
10
University of Utah, Salt Lake City.
11
Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York.
12
Stanford University, Stanford, California.
13
Hospital de Pediatria Garrahan, Buenos Aires, Argentina.
14
Universidade Federal de São Paulo, São Paulo, Brazil.
15
Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil.
16
University of Toronto, Toronto, Ontario, Canada.
17
University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
18
University College London and NIHR GOSH Biomedical Research Centre, London, UK.
19
Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.
20
German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.
21
University Hospital Cal Gustav Carus, Dresden, Germany.
22
Charité University Medicine and German Rheumatism Research Centre, Berlin, Germany.
23
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, National Institute for Health Research Manchester Biomedical Centre, Central Manchester National Health Service Foundation Trust, Manchester Academic Health Centre, University of Manchester, Manchester, UK.
24
University College London, London, UK.

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.

PMID:
29609200
PMCID:
PMC6105455
[Available on 2019-08-01]
DOI:
10.1002/art.40498

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