Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

被引：37

作者：

Lempiainen, Harri ^{[1
]}

Braenne, Ingrid ^{[2
]}

Michoel, Tom ^{[3
,4
]}

Tragante, Vinicius ^{[5
]}

Vilne, Baiba ^{[6
,7
]}

Webb, Tom R. ^{[8
,9
]}

Kyriakou, Theodosios ^{[10
]}

Eichner, Johannes ^{[1
]}

Zeng, Lingyao ^{[6
]}

Willenborg, Christina ^{[2
]}

Franzen, Oscar ^{[11
]}

Ruusalepp, Arno ^{[4
]}

Goel, Anuj ^{[10
]}

van der Laan, Sander W. ^{[12
]}

Biegert, Claudia ^{[1
]}

Hamby, Stephen ^{[8
,9
]}

Talukdar, Husain A. ^{[13
]}

Asl, Hassan Foroughi ^{[13
]}

Pasterkamp, Gerard ^{[12
,14
]}

Watkins, Hugh ^{[10
]}

Samani, Nilesh J. ^{[8
,9
]}

Wittenberger, Timo ^{[1
]}

Erdmann, Jeanette ^{[2
]}

Schunkert, Heribert ^{[6
,7
]}

Asselbergs, Folkert W. ^{[5
,15
]}

Bjorkegren, Johan L. M. ^{[4
,11
,13
]}

机构：

[1] Genedata AG, Basel, Switzerland

[2] Inst Cardiogenet, Lubeck, Germany

[3] Univ Edinburgh, Roslin Inst, Div Genet & Genom, Edinburgh, Midlothian, Scotland

[4] Clin Gene Networks AB, Stockholm, Sweden

[5] Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[6] Tech Univ Munich, Deutsch Herzzentrum Munchen, Klin Herz & Kreislauferkrankungen, Munich, Germany

[7] DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany

[8] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[9] NIHR Leicester Biomed Res Ctr, Leicester, Leics, England

[10] John Radcliffe Hosp, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England

[11] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA

[12] Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol,Lab Expt Cardiol, Utrecht, Netherlands

[13] Karolinska Univ Sjukhuset, Karolinska Inst, Dept Med, Integrated Cardiometab Ctr, Huddinge, Sweden

[14] Univ Utrecht, Univ Med Ctr Utrecht, Div Labs & Pharm, Lab Clin Chem & Hematol, Utrecht, Netherlands

[15] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

关键词：

DENSITY-LIPOPROTEIN RECEPTOR; PLASMINOGEN-ACTIVATOR; INCREASES RISK; ATHEROSCLEROSIS; EXPRESSION; MICE; LOCI; CHOLESTEROL; DALTEPARIN; BIOCONDUCTOR;

D O I：

10.1038/s41598-018-20721-6

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：

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.

引用

页数：14

共 82 条

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