Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

被引：46

作者：

Cobb, J. ^{[1
,2
]}

Cule, E. ^{[3
]}

Moncrieffe, H. ^{[4
]}

Hinks, A. ^{[1
]}

Ursu, S. ^{[4
]}

Patrick, F. ^{[4
]}

Kassoumeri, L. ^{[4
]}

Flynn, E. ^{[1
]}

Bulatovic, M. ^{[5
]}

Wulffraat, N. ^{[5
]}

van Zelst, B. ^{[6
]}

de Jonge, R. ^{[6
]}

Bohm, M. ^{[7
,8
]}

Dolezalova, P. ^{[7
,8
]}

Hirani, S. ^{[9
]}

Newman, S. ^{[9
]}

Whitworth, P. ^{[10
]}

Southwood, T. R. ^{[10
]}

De Iorio, M. ^{[11
]}

Wedderburn, L. R. ^{[4
,12
]}

Thomson, W. ^{[1
,2
]}

机构：

[1] Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Med & Human Sci, Arthrit Res UK,Ctr Genet & Genom,Inst Inflammat &, Manchester, Lancs, England

[2] Cent Manchester Natl Hlth Serv Fdn Trust, Manchester Acad Hlth Sci Ctr, NIHR Manchester Musculoskeletal Biomed Res Unit, Manchester, Lancs, England

[3] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England

[4] UCL Inst Child Hlth, Rheumatol Unit, London, England

[5] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Paediat Immunol, Utrecht, Netherlands

[6] Erasmus Univ, Med Ctr, Dept Clin Chem, Rotterdam, Netherlands

[7] Charles Univ Prague, Fac Med 1, Prague, Czech Republic

[8] Charles Univ Prague, Gen Fac Hosp, Prague, Czech Republic

[9] City Univ London, Sch Hlth Sci, Ctr Hlth Serv Res, London EC1V 0HB, England

[10] Birmingham Childrens Hosp, Inst Child Hlth, Birmingham, W Midlands, England

[11] UCL, Dept Stat Sci, London, England

[12] UCL Inst Child Hlth, Arthrit Res UK, Ctr Adolescent Rheumatol, London, England

来源：

PHARMACOGENOMICS JOURNAL | 2014年 / 14卷 / 04期

关键词：

juvenile idiopathic arthritis; methotrexate; pharmacogenetics; response; RHEUMATOID-ARTHRITIS; DISEASE-ACTIVITY; ASSOCIATION; POLYMORPHISMS; EFFICACY; PHARMACOGENETICS; CLASSIFICATION; CATEGORIES; EXPRESSION; VARIANTS;

D O I：

10.1038/tpj.2014.3

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P < 1 x 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

引用

页码：356 / 364

页数：9

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