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

Teslovich, Tanya M.; Musunuru, Kiran; Smith, Albert V.; Edmondson, Andrew C.; Stylianou, Ioannis M.; Koseki, Masahiro; Pirruccello, James P.; Ripatti, Samuli; Chasman, Daniel I. and Willer, Cristen J., et al. (2010) In Nature 466(7307). p.707-713
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... (More)
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. (Less)
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Nature
volume
466
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7307
pages
707 - 713
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Nature Publishing Group
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  • wos:000280562500029
  • scopus:77955505564
ISSN
0028-0836
DOI
10.1038/nature09270
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English
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yes
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bcb56acf-af8b-4795-9113-593c8f47c227 (old id 1677988)
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2010-09-21 10:19:51
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@article{bcb56acf-af8b-4795-9113-593c8f47c227,
  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 &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P&lt;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.},
  author       = {Teslovich, Tanya M. and Musunuru, Kiran and Smith, Albert V. and Edmondson, Andrew C. and Stylianou, Ioannis M. and Koseki, Masahiro and Pirruccello, James P. and Ripatti, Samuli and Chasman, Daniel I. and Willer, Cristen J. and Johansen, Christopher T. and Fouchier, Sigrid W. and Isaacs, Aaron and Peloso, Gina M. and Barbalic, Maja and Ricketts, Sally L. and Bis, Joshua C. and Aulchenko, Yurii S. and Thorleifsson, Gudmar and Feitosa, Mary F. and Chambers, John and Orho-Melander, Marju and Melander, Olle and Johnson, Toby and Li, Xiaohui and Guo, Xiuqing and Li, Mingyao and Cho, Yoon Shin and Go, Min Jin and Kim, Young Jin and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Ong, Rick Twee-Hee and Croteau-Chonka, Damien C. and Lange, Leslie A. and Smith, Joshua D. and Song, Kijoung and Zhao, Jing Hua and Yuan, Xin and Luan, Jian'an and Lamina, Claudia and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y. L. and Wright, Alan F. and Witteman, Jacqueline C. M. and Wilson, James F. and Willemsen, Gonneke and Wichmann, H. -Erich and Whitfield, John B. and Waterworth, Dawn M. and Wareham, Nicholas J. and Waeber, Gerard and Vollenweider, Peter and Voight, Benjamin F. and Vitart, Veronique and Uitterlinden, Andre G. and Uda, Manuela and Tuomilehto, Jaakko and Thompson, John R. and Tanaka, Toshiko and Surakka, Ida and Stringham, Heather M. and Spector, Tim D. and Soranzo, Nicole and Smit, Johannes H. and Sinisalo, Juha and Silander, Kaisa and Sijbrands, Eric J. G. and Scuteri, Angelo and Scott, James and Schlessinger, David and Sanna, Serena and Salomaa, Veikko and Saharinen, Juha and Sabatti, Chiara and Ruokonen, Aimo and Rudan, Igor and Rose, Lynda M. and Roberts, Robert and Rieder, Mark and Psaty, Bruce M. and Pramstaller, Peter P. and Pichler, Irene and Perola, Markus and Penninx, Brenda W. J. H. and Pedersen, Nancy L. and Pattaro, Cristian and Parker, Alex N. and Pare, Guillaume and Oostra, Ben A. and O'Donnell, Christopher J. and Nieminen, Markku S. and Nickerson, Deborah A. and Montgomery, Grant W. and Meitinger, Thomas and McPherson, Ruth and McCarthy, Mark I. and McArdle, Wendy and Masson, David and Martin, Nicholas G. and Marroni, Fabio and Mangino, Massimo and Magnusson, Patrik K. E. and Lucas, Gavin and Luben, Robert and Loos, Ruth J. F. and Lokki, Marja-Liisa and Lettre, Guillaume and Langenberg, Claudia and Launer, Lenore J. and Lakatta, Edward G. and Laaksonen, Reijo and Kyvik, Kirsten O. and Kronenberg, Florian and Koenig, Inke R. and Khaw, Kay-Tee and Kaprio, Jaakko and Kaplan, Lee M. and Johansson, Asa and Jarvelin, Marjo-Riitta and Janssens, A. Cecile J. W. and Ingelsson, Erik and Igi, Wilmar and Hovingh, G. Kees and Hottenga, Jouke-Jan and Hofman, Albert and Hicks, Andrew A. and Hengstenberg, Christian and Heid, Iris M. and Hayward, Caroline and Havulinna, Aki S. and Hastie, Nicholas D. and Harris, Tamara B. and Haritunians, Talin and Hall, Alistair S. and Gyllensten, Ulf and Guiducci, Candace and Groop, Leif and Gonzalez, Elena and Gieger, Christian and Freimer, Nelson B. and Ferrucci, Luigi and Erdmann, Jeanette and Elliott, Paul and Ejebe, Kenechi G. and Doering, Angela and Dominiczak, Anna F. and Demissie, Serkalem and Deloukas, Panagiotis and de Geus, Eco J. C. and de Faire, Ulf and Crawford, Gabriel and Collins, Francis S. and Chen, Yii-der I. and Caulfield, Mark J. and Campbell, Harry and Burtt, Noel P. and Bonnycastle, Lori L. and Boomsma, Dorret I. and Boekholdt, S. Matthijs and Bergman, Richard N. and Barroso, Ines and Bandinelli, Stefania and Ballantyne, Christie M. and Assimes, Themistocles L. and Quertermous, Thomas and Altshuler, David and Seielstad, Mark and Wong, Tien Y. and Tai, E-Shyong and Feranil, Alan B. and Kuzawa, Christopher W. and Adair, Linda S. and Taylor, Herman A., Jr. and Borecki, Ingrid B. and Gabriel, Stacey B. and Wilson, James G. and Holm, Hilma and Thorsteinsdottir, Unnur and Gudnason, Vilmundur and Krauss, Ronald M. and Mohlke, Karen L. and Ordovas, Jose M. and Munroe, Patricia B. and Kooner, Jaspal S. and Tall, Alan R. and Hegele, Robert A. and Kastelein, John J. P. and Schadt, Eric E. and Rotter, Jerome I. and Boerwinkle, Eric and Strachan, David P. and Mooser, Vincent and Stefansson, Kari and Reilly, Muredach P. and Samani, Nilesh J. and Schunkert, Heribert and Cupples, L. Adrienne and Sandhu, Manjinder S. and Ridker, Paul M. and Rader, Daniel J. and van Duijn, Cornelia M. and Peltonen, Leena and Abecasis, Goncalo R. and Boehnke, Michael and Kathiresan, Sekar},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7307},
  pages        = {707--713},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Biological, clinical and population relevance of 95 loci for blood lipids},
  url          = {http://dx.doi.org/10.1038/nature09270},
  volume       = {466},
  year         = {2010},
}