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Nature DOI:10.1038/nature09270

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

Publication TypeJournal Article
Year of Publication2010
AuthorsTeslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, X, Guo, X, Li, M, Cho, YShin, Go, MJin, Kim, YJin, Lee, J-Y, Park, T, Kim, K, Sim, X, Ong, RTwee-Hee, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JHua, Yuan, X, Luan, J'an, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, H-E, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, AG, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, BA, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, M-L, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, König, IR, Khaw, K-T, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, M-R, A Janssens, CJW, Ingelsson, E, Igl, W, G Hovingh, K, Hottenga, J-J, Hofman, A, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Döring, A, Dominiczak, AF, Demissie, S, Deloukas, P, De Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, Y-DI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, S Boekholdt, M, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, E-S, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, L Cupples, A, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, Kathiresan, S
JournalNature
Volume466
Issue7307
Pages707-13
Date Published2010 Aug 5
ISSN1476-4687
KeywordsAfrican Americans, Animals, Asian Continental Ancestry Group, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Europe, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, Lipids, Liver, Male, Mice, N-Acetylgalactosaminyltransferases, Phenotype, Polymorphism, Single Nucleotide, Protein Phosphatase 1, Reproducibility of Results, Triglycerides
Abstract

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.

DOI10.1038/nature09270
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/20686565?dopt=Abstract

Alternate JournalNature
PubMed ID20686565
PubMed Central IDPMC3039276
Grant List068545/Z/02 / / Wellcome Trust / United Kingdom
076113/B/04/Z / / Wellcome Trust / United Kingdom
077016/Z/05/Z / / Wellcome Trust / United Kingdom
079895 / / Wellcome Trust / United Kingdom
1Z01 HG000024 / HG / NHGRI NIH HHS / United States
5R01DK06833603 / DK / NIDDK NIH HHS / United States
5R01DK07568102 / DK / NIDDK NIH HHS / United States
5R01HL087679-02 / HL / NHLBI NIH HHS / United States
5R01HL08770003 / HL / NHLBI NIH HHS / United States
5R01HL08821502 / HL / NHLBI NIH HHS / United States
CA 047988 / CA / NCI NIH HHS / United States
CZB/4/710 / / Chief Scientist Office / United Kingdom
DK062370 / DK / NIDDK NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
DK072193 / DK / NIDDK NIH HHS / United States
DK078150 / DK / NIDDK NIH HHS / United States
DK56350 / DK / NIDDK NIH HHS / United States
ES10126 / ES / NIEHS NIH HHS / United States
G0000934 / / Medical Research Council / United Kingdom
G0401527 / / Medical Research Council / United Kingdom
G0601966 / / Medical Research Council / United Kingdom
G0700931 / / Medical Research Council / United Kingdom
G0701863 / / Medical Research Council / United Kingdom
G0801056 / / Medical Research Council / United Kingdom
G0801566 / / Medical Research Council / United Kingdom
G9521010 / / Medical Research Council / United Kingdom
G9521010D / / Medical Research Council / United Kingdom
HHSN268200625226C / / PHS HHS / United States
HL 04381 / HL / NHLBI NIH HHS / United States
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M01-RR00425 / RR / NCRR NIH HHS / United States
MC_QA137934 / / Medical Research Council / United Kingdom
MC_U106179471 / / Medical Research Council / United Kingdom
MC_U106188470 / / Medical Research Council / United Kingdom
MC_U127561128 / / Medical Research Council / United Kingdom
N01 HC-15103 / HC / NHLBI NIH HHS / United States
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N01-HG-65403 / HG / NHGRI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
PG/02/128 / / British Heart Foundation / United Kingdom
PG/08/094 / / British Heart Foundation / United Kingdom
PG/08/094/26019 / / British Heart Foundation / United Kingdom
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 DK078150 / DK / NIDDK NIH HHS / United States
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RG/07/005/23633 / / British Heart Foundation / United Kingdom
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SP/08/005/25115 / / British Heart Foundation / United Kingdom
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/ / Intramural NIH HHS / United States