International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

被引：212

作者：

Cordell, Heather J. ^{[1
]}

Han, Younghun ^{[2
]}

Mells, George F. ^{[3
]}

Li, Yafang ^{[2
]}

Hirschfield, Gideon M. ^{[4
]}

Greene, Casey S. ^{[5
]}

Xie, Gang ^{[6
,7
]}

Juran, Brian D. ^{[8
]}

Zhu, Dakai ^{[2
]}

Qian, David C. ^{[2
]}

Floyd, James A. B. ^{[9
,10
]}

Morley, Katherine I. ^{[9
,11
]}

Prati, Daniele ^{[12
]}

Lleo, Ana ^{[13
]}

Cusi, Daniele ^{[14
,15
]}

Gershwin, M. Eric ^{[16
]}

Anderson, Carl A. ^{[9
]}

Lazaridis, Konstantinos N. ^{[8
]}

Invernizzi, Pietro ^{[13
,16
]}

Seldin, Michael F. ^{[16
]}

Sandford, Richard N. ^{[3
]}

Amos, Christopher I. ^{[2
]}

Siminovitch, Katherine A. ^{[6
,7
,17
,18
,19
]}

机构：

[1] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[2] Dartmouth Coll, Dept Community & Family Med, Geisel Sch Med, Ctr Genom Med, Lebanon, NH 03755 USA

[3] Univ Cambridge, Acad Dept Med Genet, Cambridge CB2 0QQ, England

[4] Univ Birmingham, Liver Res Ctr, Birmingham B15 2TT, W Midlands, England

[5] Dartmouth Coll, Inst Quantitat Biomed Sci, Geisel Sch Med, Dept Genet, Hanover, NH 03755 USA

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

[7] Toronto Gen Res Inst, Toronto, ON M5G 1X5, Canada

[8] Mayo Clin, Ctr Basic Res Digest Dis, Rochester, MN 55905 USA

[9] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[10] Queen Mary Univ London, William Harvey Res Inst, London EC1M 6BQ, England

[11] Kings Coll London, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England

[12] Osped Alessandro Manzoni, Dept Transfus Med & Hematol, I-23900 Lecce, Italy

[13] IRCCS Inst Clin Humanitas, Ctr Autoimmune Liver Dis, I-20089 Rozzano, Italy

[14] Univ Milan, I-20129 Milan, Italy

[15] CNR, Ist Tecnol Biomed, I-20090 Milan, Italy

[16] Univ Calif Davis, Davis, CA 95616 USA

[17] Univ Toronto, Dept Med, Toronto, ON M5G 1X5, Canada

[18] Univ Toronto, Dept Immunol, Toronto, ON M5G 1X5, Canada

[19] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1X5, Canada

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

美国国家卫生研究院; 英国惠康基金; 英国医学研究理事会;

关键词：

SUSCEPTIBILITY LOCI; ASSOCIATION; VARIANTS; IMPUTATION; DATABASE; SERVER; SET;

D O I：

10.1038/ncomms9019

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：

07 ; 0710 ; 09 ;

摘要：

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n = 2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n = 3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (P-combined <5 x 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

引用

页数：11

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