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

被引：45
|
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
收藏
页码：356 / 364
页数：9
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