Genetics of rheumatoid arthritis contributes to biology and drug discovery

被引：1848

作者：

Okada, Yukinori ^{[1
,2
,3
]}

Wu, Di ^{[1
,2
,3
,4
,5
]}

Trynka, Gosia ^{[1
,2
,3
]}

Raj, Towfique ^{[2
,3
,6
]}

Terao, Chikashi ^{[7
,8
]}

Ikari, Katsunori ^{[9
]}

Kochi, Yuta ^{[10
]}

Ohmura, Koichiro ^{[8
]}

Suzuki, Akari ^{[10
]}

Yoshida, Shinji ^{[9
]}

Graham, Robert R. ^{[11
]}

Manoharan, Arun ^{[11
]}

Ortmann, Ward ^{[11
]}

Bhangale, Tushar ^{[11
]}

Denny, Joshua C. ^{[12
,13
]}

Carroll, Robert J. ^{[12
]}

Eyler, Anne E. ^{[13
]}

Greenberg, Jeffrey D. ^{[14
]}

Kremer, Joel M. ^{[15
,16
]}

Pappas, Dimitrios A. ^{[17
]}

Jiang, Lei ^{[18
]}

Yin, Jian ^{[18
]}

Ye, Lingying ^{[18
]}

Su, Ding-Feng ^{[19
]}

Yang, Jian ^{[20
,21
]}

Xie, Gang ^{[22
,23
,24
]}

Keystone, Ed ^{[25
,26
]}

Westra, Harm-Jan ^{[27
]}

Esko, Tonu ^{[3
,28
,29
]}

Metspalu, Andres ^{[28
]}

Zhou, Xuezhong ^{[30
]}

Gupta, Namrata ^{[3
]}

Mirel, Daniel ^{[3
]}

Stahl, Eli A. ^{[31
]}

Diogo, Dorothee ^{[1
,2
,3
]}

Cui, Jing ^{[1
,2
,3
]}

Liao, Katherine ^{[1
,2
,3
]}

Guo, Michael H. ^{[1
,3
,29
]}

Myouzen, Keiko ^{[10
]}

Kawaguchi, Takahisa ^{[7
]}

Coenen, Marieke J. H. ^{[32
]}

van Riel, Piet L. C. M. ^{[33
]}

van de laar, Mart A. F. J. ^{[34
,35
]}

Guchelaar, Henk-Jan ^{[36
]}

Huizinga, Tom W. J. ^{[37
]}

Dieude, Philippe ^{[38
,39
,40
]}

Mariette, Xavier ^{[41
]}

Bridges, S. Louis, Jr. ^{[42
]}

Zhernakova, Alexandra ^{[27
,37
]}

Toes, Rene E. M. ^{[37
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA

[3] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[4] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA

[5] Monash Univ, Monash Inst Med Res, Ctr Canc Res, Clayton, Vic 3800, Australia

[6] Brigham & Womens Hosp, Dept Neurol, Inst Neurosci, Programin Translat NeuroPsychiat Genom, Boston, MA 02115 USA

[7] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto 6068507, Japan

[8] Kyoto Univ, Grad Sch Med, Dept Rheumatol & Clin immunol, Kyoto 6068507, Japan

[9] Tokyo Womens Med Univ, Inst Rheumatol, Tokyo 1620054, Japan

[10] RIKEN, Ctr Integrat Med Sci, Lab Autoimmune Dis, Yokohama, Kanagawa 2300045, Japan

[11] Genentech Inc, Immunol Biomarkers Grp, San Francisco, CA 94080 USA

[12] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37232 USA

[13] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA

[14] NYU, Hosp Joint Dis, New York, NY 10003 USA

[15] Albany Med Ctr, Dept Med, Albany, NY 12206 USA

[16] Ctr Rheumatol, Albany, NY 12206 USA

[17] Columbia Univ, Coll Phys & Surg, Presbyterian Hosp, Div Rheumatol,Dept Med, New York, NY 10032 USA

[18] Second Mil Med Univ, Shanghai Changzheng Hosp, Dept Rheumatol & Immunol, Shanghai 200003, Peoples R China

[19] Second Mil Med Univ, Dept Pharmacol, Shanghai 200433, Peoples R China

[20] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4072, Australia

[21] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[22] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[23] Toronto Gen Res Inst, Toronto, ON M5G 2M9, Canada

[24] Univ Toronto, Dept Med, Toronto, ON M5S 2J7, Canada

[25] Mt Sinai Hosp, Dept Med, Toronto, ON M5S 2J7, Canada

[26] Univ Toronto, Toronto, ON M5S 2J7, Canada

[27] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[28] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia

[29] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[30] Beijing Jiaotong Univ, Sch Comp & Informat Technol, Beijing 100044, Peoples R China

[31] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA

[32] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[33] Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, NL-6500 HB Nijmegen, Netherlands

[34] Univ Twente, Arthrit Ctr Twente, Dept Rheumatol & Clin Immunol, NL-7500 AE Enschede, Netherlands

[35] Med Spectrum Twente, NL-7500 AE Enschede, Netherlands

[36] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, NL-2300 RC Leiden, Netherlands

[37] Leiden Univ, Med Ctr, Dept Rheumatol, NL-2300 RC Leiden, Netherlands

[38] Hop Bichat Claude Bernard, AP HP, Serv Rhumatol, F-75018 Paris, France

[39] Hop Bichat Claude Bernard, AP HP, INSERM, U699, F-75018 Paris, France

[40] Univ Paris 07, F-75013 Paris, France

[41] Univ Paris 11, Hop Univ Paris Sud, AP HP, INSERM,U1012, F-94275 Le Kremlin Bicetre, France

[42] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA

[43] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands

[44] GlaxoSmithKline, Stevenage SG1 2NY, Herts, England

[45] Univ Cambridge, Cambridge CB2 1TN, England

[46] Hanyang Univ, Hosp Rheumat Dis, Dept Rheumatol, Seoul 133792, South Korea

[47] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain

[48] Hosp Marques de Valdecilla, IFIMAV, Dept Rheumatol, Santander 39008, Spain

[49] Hosp Clin San Carlos, Madrid 28040, Spain

[50] Umea Univ, Dept Publ Hlth & Clin Med, SE-90187 Umea, Sweden

来源：

NATURE | 2014年 / 506卷 / 7488期

基金：

中国国家自然科学基金; 欧洲研究理事会; 英国医学研究理事会; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; RECEPTOR INHIBITION; LOCI; RISK; SUSCEPTIBILITY; IDENTIFICATION; RESOURCE;

D O I：

10.1038/nature12873

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

引用

页码：376 / +

页数：21

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