| Biological, clinical and population relevance of 95 loci for blood lipids. | |
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MedLine Citation:
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PMID: 20686565 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Tanya M Teslovich; Kiran Musunuru; Albert V Smith; Andrew C Edmondson; Ioannis M Stylianou; Masahiro Koseki; James P Pirruccello; Samuli Ripatti; Daniel I Chasman; Cristen J Willer; Christopher T Johansen; Sigrid W Fouchier; Aaron Isaacs; Gina M Peloso; Maja Barbalic; Sally L Ricketts; Joshua C Bis; Yurii S Aulchenko; Gudmar Thorleifsson; Mary F Feitosa; John Chambers; Marju Orho-Melander; Olle Melander; Toby Johnson; Xiaohui Li; Xiuqing Guo; Mingyao Li; Yoon Shin Cho; Min Jin Go; Young Jin Kim; Jong-Young Lee; Taesung Park; Kyunga Kim; Xueling Sim; Rick Twee-Hee Ong; Damien C Croteau-Chonka; Leslie A Lange; Joshua D Smith; Kijoung Song; Jing Hua Zhao; Xin Yuan; Jian'an Luan; Claudia Lamina; Andreas Ziegler; Weihua Zhang; Robert Y L Zee; Alan F Wright; Jacqueline C M Witteman; James F Wilson; Gonneke Willemsen; H-Erich Wichmann; John B Whitfield; Dawn M Waterworth; Nicholas J Wareham; Gérard Waeber; Peter Vollenweider; Benjamin F Voight; Veronique Vitart; Andre G Uitterlinden; Manuela Uda; Jaakko Tuomilehto; John R Thompson; Toshiko Tanaka; Ida Surakka; Heather M Stringham; Tim D Spector; Nicole Soranzo; Johannes H Smit; Juha Sinisalo; Kaisa Silander; Eric J G Sijbrands; Angelo Scuteri; James Scott; David Schlessinger; Serena Sanna; Veikko Salomaa; Juha Saharinen; Chiara Sabatti; Aimo Ruokonen; Igor Rudan; Lynda M Rose; Robert Roberts; Mark Rieder; Bruce M Psaty; Peter P Pramstaller; Irene Pichler; Markus Perola; Brenda W J H Penninx; Nancy L Pedersen; Cristian Pattaro; Alex N Parker; Guillaume Pare; Ben A Oostra; Christopher J O'Donnell; Markku S Nieminen; Deborah A Nickerson; Grant W Montgomery; Thomas Meitinger; Ruth McPherson; Mark I McCarthy; Wendy McArdle; David Masson; Nicholas G Martin; Fabio Marroni; Massimo Mangino; Patrik K E Magnusson; Gavin Lucas; Robert Luben; Ruth J F Loos; Marja-Liisa Lokki; Guillaume Lettre; Claudia Langenberg; Lenore J Launer; Edward G Lakatta; Reijo Laaksonen; Kirsten O Kyvik; Florian Kronenberg; Inke R König; Kay-Tee Khaw; Jaakko Kaprio; Lee M Kaplan; Asa Johansson; Marjo-Riitta Jarvelin; A Cecile J W Janssens; Erik Ingelsson; Wilmar Igl; G Kees Hovingh; Jouke-Jan Hottenga; Albert Hofman; Andrew A Hicks; Christian Hengstenberg; Iris M Heid; Caroline Hayward; Aki S Havulinna; Nicholas D Hastie; Tamara B Harris; Talin Haritunians; Alistair S Hall; Ulf Gyllensten; Candace Guiducci; Leif C Groop; Elena Gonzalez; Christian Gieger; Nelson B Freimer; Luigi Ferrucci; Jeanette Erdmann; Paul Elliott; Kenechi G Ejebe; Angela Döring; Anna F Dominiczak; Serkalem Demissie; Panagiotis Deloukas; Eco J C de Geus; Ulf de Faire; Gabriel Crawford; Francis S Collins; Yii-der I Chen; Mark J Caulfield; Harry Campbell; Noel P Burtt; Lori L Bonnycastle; Dorret I Boomsma; S Matthijs Boekholdt; Richard N Bergman; Inês Barroso; Stefania Bandinelli; Christie M Ballantyne; Themistocles L Assimes; Thomas Quertermous; David Altshuler; Mark Seielstad; Tien Y Wong; E-Shyong Tai; Alan B Feranil; Christopher W Kuzawa; Linda S Adair; Herman A Taylor; Ingrid B Borecki; Stacey B Gabriel; James G Wilson; Hilma Holm; Unnur Thorsteinsdottir; Vilmundur Gudnason; Ronald M Krauss; Karen L Mohlke; Jose M Ordovas; Patricia B Munroe; Jaspal S Kooner; Alan R Tall; Robert A Hegele; John J P Kastelein; Eric E Schadt; Jerome I Rotter; Eric Boerwinkle; David P Strachan; Vincent Mooser; Kari Stefansson; Muredach P Reilly; Nilesh J Samani; Heribert Schunkert; L Adrienne Cupples; Manjinder S Sandhu; Paul M Ridker; Daniel J Rader; Cornelia M van Duijn; Leena Peltonen; Gonçalo R Abecasis; Michael Boehnke; Sekar Kathiresan |
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Publication Detail:
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Type: Journal Article; Meta-Analysis; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 466 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-05 Completed Date: 2010-09-24 Revised Date: 2011-10-11 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 707-13 Citation Subset: IM |
Affiliation:
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Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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African Americans
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genetics Animals Asian Continental Ancestry Group / genetics Cholesterol, HDL / blood Cholesterol, LDL / blood Coronary Artery Disease / blood, genetics, therapy Europe / ethnology European Continental Ancestry Group / genetics Female Genetic Loci / genetics* Genome-Wide Association Study* Genotype Humans Lipid Metabolism / genetics* Lipids / blood* Liver / metabolism Male Mice N-Acetylgalactosaminyltransferases / genetics, metabolism Phenotype Polymorphism, Single Nucleotide / genetics Protein Phosphatase 1 / genetics, metabolism Reproducibility of Results Triglycerides / blood |
| Grant Support | |
ID/Acronym/Agency:
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068545/Z/02//Wellcome Trust; 076113/B/04/Z//Wellcome Trust; 077016/Z/05/Z//Wellcome Trust; 079895//Wellcome Trust; 1Z01 HG000024/HG/NHGRI NIH HHS; 5R01DK06833603/DK/NIDDK NIH HHS; 5R01DK07568102/DK/NIDDK NIH HHS; 5R01HL087679-02/HL/NHLBI NIH HHS; 5R01HL08770003/HL/NHLBI NIH HHS; 5R01HL08821502/HL/NHLBI NIH HHS; CA 047988/CA/NCI NIH HHS; DK062370/DK/NIDDK NIH HHS; DK063491/DK/NIDDK NIH HHS; DK072193/DK/NIDDK NIH HHS; DK078150/DK/NIDDK NIH HHS; DK56350/DK/NIDDK NIH HHS; ES10126/ES/NIEHS NIH HHS; G0000934//Medical Research Council; G0801566//Medical Research Council; G9521010//Medical Research Council; G9521010D//Medical Research Council; HHSN268200625226C//PHS HHS; HL 04381/HL/NHLBI NIH HHS; HL 080467/HL/NHLBI NIH HHS; HL-54776/HL/NHLBI NIH HHS; HL085144/HL/NHLBI NIH HHS; K99 HL098364/HL/NHLBI NIH HHS; K99 HL098364-01/HL/NHLBI NIH HHS; K99 HL098364-02/HL/NHLBI NIH HHS; K99HL094535/HL/NHLBI NIH HHS; M01-RR00425/RR/NCRR NIH HHS; N01 HC-15103/HC/NHLBI NIH HHS; N01 HC-55222/HC/NHLBI NIH HHS; N01-AG-12100/AG/NIA NIH HHS; N01-HC-25195/HC/NHLBI NIH HHS; N01-HC-35129/HC/NHLBI NIH HHS; N01-HC-45133/HC/NHLBI NIH HHS; N01-HC-55015/HC/NHLBI NIH HHS; N01-HC-55016/HC/NHLBI NIH HHS; N01-HC-55018/HC/NHLBI NIH HHS; N01-HC-55019/HC/NHLBI NIH HHS; N01-HC-55020/HC/NHLBI NIH HHS; N01-HC-55021/HC/NHLBI NIH HHS; N01-HC-55022/HC/NHLBI NIH HHS; N01-HC-75150/HC/NHLBI NIH HHS; N01-HC-85079/HC/NHLBI NIH HHS; N01-HC-85080/HC/NHLBI NIH HHS; N01-HC-85081/HC/NHLBI NIH HHS; N01-HC-85082/HC/NHLBI NIH HHS; N01-HC-85083/HC/NHLBI NIH HHS; N01-HC-85084/HC/NHLBI NIH HHS; N01-HC-85085/HC/NHLBI NIH HHS; N01-HC-85086/HC/NHLBI NIH HHS; N01-HG-65403/HG/NHGRI NIH HHS; N02-HL-6-4278/HL/NHLBI NIH HHS; PG/02/128//British Heart Foundation; PG/08/094//British Heart Foundation; R01 HL087676/HL/NHLBI NIH HHS; R01 HL089650/HL/NHLBI NIH HHS; R01HL086694/HL/NHLBI NIH HHS; R01HL087641/HL/NHLBI NIH HHS; R01HL087652/HL/NHLBI NIH HHS; R01HL59367/HL/NHLBI NIH HHS; R24 HD050924-07/HD/NICHD NIH HHS; RC1 HL099634/HL/NHLBI NIH HHS; RC1 HL099634-02/HL/NHLBI NIH HHS; RC1 HL099793/HL/NHLBI NIH HHS; RC2 HL101864,/HL/NHLBI NIH HHS; RC2 HL102419/HL/NHLBI NIH HHS; RG/07/005/23633//British Heart Foundation; RR20649/RR/NCRR NIH HHS; SP/08/005/25115//British Heart Foundation; T32 GM007092/GM/NIGMS NIH HHS; T32 HG00040/HG/NHGRI NIH HHS; T32HL007208/HL/NHLBI NIH HHS; TW05596/TW/FIC NIH HHS; U01 DK062370/DK/NIDDK NIH HHS; U01 DK062418/DK/NIDDK NIH HHS; U01 HL069757/HL/NHLBI NIH HHS; U01 HL080295/HL/NHLBI NIH HHS; U01HG004402/HG/NHGRI NIH HHS; U54 RR020278/RR/NCRR NIH HHS; UL1RR025005/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cholesterol, HDL; 0/Cholesterol, LDL; 0/Lipids; 0/Triglycerides; EC 2.4.1.-/N-Acetylgalactosaminyltransferases; EC 2.4.1.41/polypeptide N-acetylgalactosaminyltransferase; EC 3.1.3.16/Ppp1r3b protein, mouse; EC 3.1.3.16/Protein Phosphatase 1 |
| Comments/Corrections | |
Comment In:
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Nature. 2010 Aug 5;466(7307):703-4
[PMID:
20686562
]
Am J Transplant. 2011 Sep;11(9):1763 [PMID: 21884406 ] Nat Rev Endocrinol. 2010 Nov;6(11):598 [PMID: 21038508 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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