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Biological, clinical and population relevance of 95 loci for blood lipids.
Tuesday,2012-11-06 12:19 America/Los_Angeles — eenright
| Title | Biological, clinical and population relevance of 95 loci for blood lipids. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Teslovich, 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, Paré, 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-derI, 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, Cupples, AL, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, Kathiresan, S |
| Journal | Nature |
| Volume | 466 |
| Issue | 7307 |
| Pagination | 707-13 |
| Date Published | 2010 Aug 05 |
| ISSN | 1476-4687 |
| Keywords | African 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 | <p>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.</p> |
| DOI | 10.1038/nature09270 |
| Alternate Journal | Nature |
| PubMed ID | 20686565 |
| PubMed Central ID | PMC3039276 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States DK078150 / DK / NIDDK NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States CZB/4/710 / / Chief Scientist Office / United Kingdom R01 HL087676 / HL / NHLBI NIH HHS / United States K99HL094535 / HL / NHLBI NIH HHS / United States G0801056 / / Medical Research Council / United Kingdom RC1 HL099634-02 / HL / NHLBI NIH HHS / United States R01 HL087647 / HL / NHLBI NIH HHS / United States G0801566 / / Medical Research Council / United Kingdom N01-HC-85085 / HC / NHLBI NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States RG/07/005/23633 / / British Heart Foundation / United Kingdom RC2 HL102419 / HL / NHLBI NIH HHS / United States RC1 HL099793 / HL / NHLBI NIH HHS / United States T32 HG00040 / HG / NHGRI NIH HHS / United States N01-HC-55022 / HC / NHLBI NIH HHS / United States N01-HC-85081 / HC / NHLBI NIH HHS / United States U54 RR020278 / RR / NCRR NIH HHS / United States MC_U127561128 / / Medical Research Council / United Kingdom G0700931 / / Medical Research Council / United Kingdom 079895 / / Wellcome Trust / United Kingdom N01-HC-55016 / HC / NHLBI NIH HHS / United States 1Z01 HG000024 / HG / NHGRI NIH HHS / United States HL 080467 / HL / NHLBI NIH HHS / United States G9521010D / / Medical Research Council / United Kingdom R01 DK072193 / DK / NIDDK NIH HHS / United States T32 GM007092 / GM / NIGMS NIH HHS / United States RC2 HL101864, / HL / NHLBI NIH HHS / United States RC1 HL099634 / HL / NHLBI NIH HHS / United States HHSN268200625226C / / PHS HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States ES10126 / ES / NIEHS NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States G0601966 / / Medical Research Council / United Kingdom TW05596 / TW / FIC NIH HHS / United States U01HG004402 / HG / NHGRI NIH HHS / United States RC1 HL099634-02 / RC / CCR NIH HHS / United States CA 047988 / CA / NCI NIH HHS / United States T32 HL007208 / HL / NHLBI NIH HHS / United States DK072193 / DK / NIDDK NIH HHS / United States MC_U106179471 / / Medical Research Council / United Kingdom HL-54776 / HL / NHLBI NIH HHS / United States DK56350 / DK / NIDDK NIH HHS / United States N01-HC-85082 / HC / NHLBI NIH HHS / United States RR20649 / RR / NCRR NIH HHS / United States / / Intramural NIH HHS / United States N01-HC-35129 / HC / NHLBI NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States HL085144 / HL / NHLBI NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States G0401527 / / Medical Research Council / United Kingdom G0701863 / / Medical Research Council / United Kingdom G9521010 / / Medical Research Council / United Kingdom SP/08/005/25115 / / British Heart Foundation / United Kingdom N01-HC-85083 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01-HC-85080 / HC / NHLBI NIH HHS / United States N01 HC-15103 / HC / NHLBI NIH HHS / United States U01 HL069757 / HL / NHLBI NIH HHS / United States PG/02/128 / / British Heart Foundation / United Kingdom 5R01HL08821502 / HL / NHLBI NIH HHS / United States R01 HL089650 / HL / NHLBI NIH HHS / United States K99 HL098364 / HL / NHLBI NIH HHS / United States DK062370 / DK / NIDDK NIH HHS / United States R01HL087652 / HL / NHLBI NIH HHS / United States N01-AG-12100 / AG / NIA NIH HHS / United States PG/08/094/26019 / / British Heart Foundation / United Kingdom 5R01HL08770003 / HL / NHLBI NIH HHS / United States T32HL007208 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-45133 / HC / NHLBI NIH HHS / United States K99 HL098364-01 / HL / NHLBI NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States 068545/Z/02 / / Wellcome Trust / United Kingdom 5R01HL087679-02 / HL / NHLBI NIH HHS / United States MC_QA137934 / / Medical Research Council / United Kingdom PG/08/094 / / British Heart Foundation / United Kingdom R24 HD050924 / HD / NICHD NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States HL 04381 / HL / NHLBI NIH HHS / United States MC_U106188470 / / Medical Research Council / United Kingdom 076113/B/04/Z / / Wellcome Trust / United Kingdom 077016/Z/05/Z / / Wellcome Trust / United Kingdom G0000934 / / Medical Research Council / United Kingdom 5R01DK07568102 / DK / NIDDK NIH HHS / United States R01 DK078150 / DK / NIDDK NIH HHS / United States N01-HC-85084 / HC / NHLBI NIH HHS / United States U01 DK062418 / DK / NIDDK NIH HHS / United States 5R01DK06833603 / DK / NIDDK NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States N01-HG-65403 / HG / NHGRI NIH HHS / United States |