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

被引：40

作者：

Arthur, Victoria L. ^{[1
]}

Shuldiner, Emily ^{[1
]}

Remmers, Elaine F. ^{[2
]}

Hinks, Anne ^{[3
]}

Grom, Alexei A. ^{[4
,5
]}

Foell, Dirk ^{[6
]}

Martini, Alberto ^{[7
,8
]}

Gattorno, Marco

Ozen, Seza ^{[9
]}

Prahalad, Sampath ^{[10
,11
]}

Zeft, Andrew S. ^{[12
]}

Bohnsack, John F. ^{[13
]}

Ilowite, Norman T. ^{[14
,15
]}

Mellins, Elizabeth D. ^{[16
]}

Russo, Ricardo ^{[17
]}

Len, Claudio ^{[18
]}

Oliveira, Sheila ^{[19
]}

Yeung, Rae S. M. ^{[20
]}

Rosenberg, Alan M. ^{[21
]}

Wedderburn, Lucy R. ^{[22
,23
]}

Anton, Jordi ^{[24
]}

Haas, Johannes-Peter ^{[25
]}

Roesen-Wolff, Angela ^{[26
]}

Minden, Kirsten ^{[27
,28
]}

Szymanski, Ann Marie ^{[1
]}

Thomson, Wendy ^{[29
]}

Kastner, Daniel L. ^{[2
]}

Woo, Patricia ^{[22
]}

Ombrello, Michael J. ^{[1
]}

机构：

[1] NIAMSD, NIH, Bethesda, MD 20892 USA

[2] NHGRI, NIH, Bethesda, MD 20892 USA

[3] Univ Manchester, Ctr Musculoskeletal Res, Arthrit Res UK Ctr Genet & Genom, Manchester, Lancs, England

[4] Univ Cincinnati, Coll Med, Cincinnati, OH USA

[5] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[6] Univ Hosp Munster, Munster, Germany

[7] G Gaslini Inst Children, Genoa, Italy

[8] Univ Genoa, Genoa, Italy

[9] Hacettepe Univ, Ankara, Turkey

[10] Emory Univ, Sch Med, Atlanta, GA 30322 USA

[11] Childrens Healthcare Atlanta, Atlanta, GA USA

[12] Cleveland Clin, Cleveland, OH 44106 USA

[13] Univ Utah, Salt Lake City, UT USA

[14] Albert Einstein Coll Med, Bronx, NY 10467 USA

[15] Childrens Hosp Montefiore, Bronx, NY USA

[16] Stanford Univ, Stanford, CA 94305 USA

[17] Hosp Pediat Garrahan, Buenos Aires, DF, Argentina

[18] Univ Fed Sao Paulo, Sao Paulo, Brazil

[19] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil

[20] Univ Toronto, Toronto, ON, Canada

[21] Univ Saskatchewan, Saskatoon, SK, Canada

[22] UCL, London, England

[23] NIHR, GOSH, Biomed Res Ctr, London, England

[24] Univ Barcelona, Hosp St Joan Deu, Barcelona, Spain

[25] German Ctr Pediat & Adolescent Rheumatol, Garmisch Partenkirchen, Germany

[26] Univ Hosp Cal Gustav Carus, Dresden, Germany

[27] Charite, Berlin, Germany

[28] German Rheumatism Res Ctr, Berlin, Germany

[29] Univ Manchester, Cent Manchester NHS Fdn Trust, Arthrit Res UK Ctr Genet & Genom,Ctr Musculoskele, NIHR Manchester Biomed Ctr,Manchester Acad Hlth C, Manchester, Lancs, England

来源：

ARTHRITIS & RHEUMATOLOGY | 2018年 / 70卷 / 08期

基金：

英国医学研究理事会; 英国惠康基金; 加拿大健康研究院;

关键词：

GENE-EXPRESSION PROFILES; PERIPHERAL-BLOOD; ASSOCIATION; VARIANTS; POLYMORPHISMS; ACTIVATION; CHILDREN; FAMILY;

D O I：

10.1002/art.40498

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1319 / 1330

页数：12

共 39 条

[1] A global reference for human genetic variation [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Wang, Jun ;

Wilson, Richard K. ;

Boerwinkle, Eric ;

Doddapaneni, Harsha ;

Han, Yi ;

Korchina, Viktoriya ;

Kovar, Christie ;

Lee, Sandra ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Zhu, Yiming ;

Chang, Yuqi ;

Feng, Qiang ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Lan, Tianming ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Liu, Shengmao ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Tang, Meifang ;

Wang, Bo .

NATURE, 2015, 526 (7571) :68-+

[2] Subtype-Specific Peripheral Blood Gene Expression Profiles in Recent-Onset Juvenile Idiopathic Arthritis [J].

Barnes, Michael G. ;

Grom, Alexei A. ;

Thompson, Susan D. ;

Griffin, Thomas A. ;

Pavlidis, Paul ;

Itert, Lukasz ;

Fall, Ndate ;

Sowders, Dawn Paxson ;

Hinze, Claas H. ;

Aronow, Bruce J. ;

Luyrink, Lorie K. ;

Srivastava, Shweta ;

Ilowite, Norman T. ;

Gottlieb, Beth S. ;

Olson, Judyann C. ;

Sherry, David D. ;

Glass, David N. ;

Colbert, Robert A. .

ARTHRITIS AND RHEUMATISM, 2009, 60 (07) :2102-2112

[3] Haploview: analysis and visualization of LD and haplotype maps [J].

Barrett, JC ;

Fry, B ;

Maller, J ;

Daly, MJ .

BIOINFORMATICS, 2005, 21 (02) :263-265

[4]

Beukelman Timothy, 2014, F1000Prime Rep, V6, P21, DOI 10.12703/P6-21

[5] Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case-control study [J].

Bukulmez, H ;

Fife, M ;

Tsoras, M ;

Thompson, SD ;

Twine, NA ;

Woo, P ;

Olson, JM ;

Elston, RC ;

Glass, DN ;

Colbert, RA .

ARTHRITIS RESEARCH & THERAPY, 2005, 7 (02) :R285-R290

[6] Systemic-onset juvenile idiopathic arthritis [J].

Cimaz, Rolando .

AUTOIMMUNITY REVIEWS, 2016, 15 (09) :931-934

[7] Functional and prognostic relevance of the-173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis [J].

De Benedetti, F ;

Meazza, C ;

Vivarelli, M ;

Rossi, F ;

Pistorio, A ;

Lamb, R ;

Lunt, M ;

Thomson, W ;

Ravelli, A ;

Donn, R ;

Martini, A .

ARTHRITIS AND RHEUMATISM, 2003, 48 (05) :1398-1407

[8]

DEBenedetti F, 1995, CLIN EXP RHEUMATOL, V13, P779

[9] Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome [J].

Fall, Ndate ;

Barnes, Michael ;

Thornton, Sherry ;

Luyrink, Lorie ;

Olson, Judyann ;

Ilowite, Norman T. ;

Gottlieb, Beth S. ;

Griffin, Thomas ;

Sherry, David D. ;

Thompson, Susan ;

Glass, David N. ;

Colbert, Robert A. ;

Grom, Alexei A. .

ARTHRITIS AND RHEUMATISM, 2007, 56 (11) :3793-3804

[10] Evaluating historical candidate genes for schizophrenia [J].

Farrell, M. S. ;

Werge, T. ;

Sklar, P. ;

Owen, M. J. ;

Ophoff, R. A. ;

O'Donovan, M. C. ;

Corvin, A. ;

Cichon, S. ;

Sullivan, P. F. .

MOLECULAR PSYCHIATRY, 2015, 20 (05) :555-562

← 1 2 3 4 →