Biological, clinical and population relevance of 95 loci for blood lipids

被引：2816

作者：

Teslovich, Tanya M. ^{[2
]}

Musunuru, Kiran ^{[1
,3
,4
,5
,6
]}

Smith, Albert V. ^{[7
,8
]}

Edmondson, Andrew C. ^{[9
,10
]}

Stylianou, Ioannis M. ^{[10
]}

Koseki, Masahiro ^{[11
]}

Pirruccello, James P. ^{[1
,4
,6
]}

Ripatti, Samuli ^{[12
,13
]}

Chasman, Daniel I. ^{[5
,14
]}

Willer, Cristen J. ^{[2
]}

Johansen, Christopher T. ^{[15
]}

Fouchier, Sigrid W. ^{[16
]}

Isaacs, Aaron ^{[17
]}

Peloso, Gina M. ^{[18
,19
]}

Barbalic, Maja ^{[20
]}

Ricketts, Sally L. ^{[21
]}

Bis, Joshua C. ^{[22
,23
]}

Aulchenko, Yurii S. ^{[17
]}

Thorleifsson, Gudmar ^{[24
]}

Feitosa, Mary F. ^{[25
]}

Chambers, John ^{[26
]}

Orho-Melander, Marju ^{[27
]}

Melander, Olle ^{[27
]}

Johnson, Toby ^{[28
]}

Li, Xiaohui ^{[29
]}

Guo, Xiuqing ^{[29
]}

Li, Mingyao ^{[9
,10
]}

Cho, Yoon Shin ^{[30
]}

Go, Min Jin ^{[30
]}

Kim, Young Jin ^{[30
]}

Lee, Jong-Young ^{[30
]}

Park, Taesung ^{[31
,32
]}

Kim, Kyunga ^{[33
]}

Sim, Xueling ^{[34
]}

Ong, Rick Twee-Hee ^{[36
]}

Croteau-Chonka, Damien C. ^{[35
]}

Lange, Leslie A. ^{[35
]}

Smith, Joshua D. ^{[37
]}

Song, Kijoung ^{[38
]}

Zhao, Jing Hua ^{[39
]}

Yuan, Xin ^{[38
]}

Luan, Jian'an ^{[39
]}

Lamina, Claudia ^{[40
]}

Ziegler, Andreas ^{[41
]}

Zhang, Weihua ^{[26
]}

Zee, Robert Y. L. ^{[5
,14
]}

Wright, Alan F. ^{[42
]}

Witteman, Jacqueline C. M. ^{[17
,43
,44
]}

Wilson, James F. ^{[45
]}

Willemsen, Gonneke ^{[46
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[2] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[3] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[4] Broad Inst, Cambridge, MA 02142 USA

[5] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[6] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA

[7] Iceland Heart Assoc, Heart Prevent Clin & Res Inst, IS-201 Kopavogur, Iceland

[8] Univ Iceland, IS-101 Reykjavik, Iceland

[9] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[10] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

[11] Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA

[12] Univ Helsinki, FIMM, FI-00014 Helsinki, Finland

[13] Natl Inst Hlth & Welf, FI-00251 Helsinki, Finland

[14] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA

[15] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8, Canada

[16] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands

[17] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

[18] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[19] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA

[20] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[21] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England

[22] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA

[23] Univ Washington, Dept Med, Seattle, WA 98101 USA

[24] DeCODE, IS-101 Reykjavik, Iceland

[25] Washington Univ, Sch Med, Div Stat Genom, Ctr Genome Sci, St Louis, MO 63108 USA

[26] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England

[27] Lund Univ, Dept Clin Sci, SE-20502 Malmo, Sweden

[28] Queen Mary Univ London, Clin Pharmacol & Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med, London EC1M 6BQ, England

[29] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[30] Natl Inst Hlth, Ctr Genome Sci, Seoul 122701, South Korea

[31] Seoul Natl Univ, Coll Nat Sci, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea

[32] Seoul Natl Univ, Coll Nat Sci, Dept Stat, Seoul 151742, South Korea

[33] Sookmyung Womens Univ, Dept Stat, Seoul 140742, South Korea

[34] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117597, Singapore

[35] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[36] Genome Inst Singapore, Singapore 138672, Singapore

[37] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[38] GlaxoSmithKline R&D, Div Genet, King Of Prussia, PA 19406 USA

[39] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England

[40] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, A-6020 Innsbruck, Austria

[41] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23562 Lubeck, Germany

[42] Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[43] NGI, NCHA, NL-2300 RC Leiden, Netherlands

[44] CMSB, NL-2300 RC Leiden, Netherlands

[45] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland

[46] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands

[47] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany

[48] PO Royal Brisbane Hosp, Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4029, Australia

[49] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland

[50] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands

来源：

NATURE | 2010年 / 466卷 / 7307期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; DISEASE; RISK; TRAITS; TRIGLYCERIDES; CHOLESTEROL; HUMANS;

D O I：

10.1038/nature09270

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：

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

引用

页码：707 / 713

页数：7

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