Cited by 3,487Genetic Associations and EpidemiologyLipoproteins and Cardiovascular HealthLipid metabolism and disorders

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

Open access
Teslovich, Tanya M., Musunuru, Kiran, Smith, Albert V., Edmondson, Andrew C., Stylianou, Ioannis M., Koseki, Masahiro, Pirruccello, James P., Ripatti, Samuli, Chasman, Daniel I., Willer, Cristen J., Johansen, Christopher T., Fouchier, Sigrid W., Isaacs, Aaron, Peloso, Gina M., Barbalic, Maja, Ricketts, Sally L., Bis, Joshua C., Aulchenko, Yurii S., Thorleifsson, Gudmar, Feitosa, Mary F., Chambers, John, Orho-Melander, Marju, Melander, Olle, Johnson, Toby, Li, Xiaohui, Guo, Xiuqing, Li, Mingyao, Shin Cho, Yoon, Jin Go, Min, Jin Kim, Young, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Twee-Hee Ong, Rick, Croteau-Chonka, Damien C., Lange, Leslie A., Smith, Joshua D., Song, Kijoung, Hua Zhao, Jing, Yuan, Xin, Luan, Jian’an, Lamina, Claudia, Ziegler, Andreas, Zhang, Weihua, Zee, Robert Y. L., Wright, Alan F., Witteman, Jacqueline C. M., Wilson, James F., Willemsen, Gonneke, Wichmann, H.-Erich, Whitfield, John B., Waterworth, Dawn M., Wareham, Nicholas J., Waeber, Gérard, Vollenweider, Peter, Voight, Benjamin F., Vitart, Veronique, Uitterlinden, Andre G., Uda, Manuela, Tuomilehto, Jaakko, Thompson, John R., Tanaka, Toshiko, Surakka, Ida, Stringham, Heather M., Spector, Tim D., Soranzo, Nicole, Smit, Johannes H., Sinisalo, Juha, Silander, Kaisa, Sijbrands, Eric J. G., Scuteri, Angelo, Scott, James, Schlessinger, David, Sanna, Serena, Salomaa, Veikko, Saharinen, Juha, Sabatti, Chiara, Ruokonen, Aimo, Rudan, Igor, Rose, Lynda M., Roberts, Robert, Rieder, Mark, Psaty, Bruce M., Pramstaller, Peter P., Pichler, Irene, Perola, Markus, Penninx, Brenda W. J. H., Pedersen, Nancy L., Pattaro, Cristian, Parker, Alex N., Pare, Guillaume, Oostra, Ben A., O’Donnell, Christopher J., Nieminen, Markku S., Nickerson, Deborah A., Montgomery, Grant W., Meitinger, Thomas, McPherson, Ruth, McCarthy, Mark I., McArdle, Wendy, Masson, David, Martin, Nicholas G., Marroni, Fabio, Mangino, Massimo, Magnusson, Patrik K. E., Lucas, Gavin, Luben, Robert, Loos, Ruth J. F., Lokki, Marja-Liisa, Lettre, Guillaume, Langenberg, Claudia, Launer, Lenore J., Lakatta, Edward G., Laaksonen, Reijo, Kyvik, Kirsten O., Kronenberg, Florian, König, Inke R., Khaw, Kay-Tee, Kaprio, Jaakko, Kaplan, Lee M., Johansson, Åsa, Jarvelin, Marjo-Riitta, Cecile J. W. Janssens, A., Ingelsson, Erik, Igl, Wilmar, Kees Hovingh, G., Hottenga, Jouke-Jan, Hofman, Albert, Hicks, Andrew A., Hengstenberg, Christian, Heid, Iris M., Hayward, Caroline, Havulinna, Aki S., Hastie, Nicholas D., Harris, Tamara B., Haritunians, Talin, Hall, Alistair S., Gyllensten, Ulf, Guiducci, Candace, Groop, Leif C., Gonzalez, Elena, Gieger, Christian, Freimer, Nelson B., Ferrucci, Luigi, Erdmann, Jeanette, Elliott, Paul, Ejebe, Kenechi G., Döring, Angela, Dominiczak, Anna F., Demissie, Serkalem, Deloukas, Panagiotis, de Geus, Eco J. C., de Faire, Ulf, Crawford, Gabriel, Collins, Francis S., Chen, Yii-der I., Caulfield, Mark J., Campbell, Harry, Burtt, Noel P., Bonnycastle, Lori L., Boomsma, Dorret I., Boekholdt, S. Matthijs, Bergman, Richard N., Barroso, Inês, Bandinelli, Stefania, Ballantyne, Christie M., Assimes, Themistocles L., Quertermous, Thomas, Altshuler, David, Seielstad, Mark, Wong, Tien Y., Tai, E-Shyong, Feranil, Alan B., Kuzawa, Christopher W., Adair, Linda S., Taylor Jr, Herman A., Borecki, Ingrid B., Gabriel, Stacey B., Wilson, James G., Holm, Hilma, Thorsteinsdottir, Unnur, Gudnason, Vilmundur, Krauss, Ronald M., Mohlke, Karen L., Ordovas, Jose M., Munroe, Patricia B., Kooner, Jaspal S., Tall, Alan R., Hegele, Robert A., Kastelein, John J.P., Schadt, Eric E., Rotter, Jerome I., Boerwinkle, Eric, Strachan, David P., Mooser, Vincent, Stefansson, Kari, Reilly, Muredach P., Samani, Nilesh J, Schunkert, Heribert, Cupples, L. Adrienne, Sandhu, Manjinder S., Ridker, Paul M, Rader, Daniel J., van Duijn, Cornelia M., Peltonen, Leena, Abecasis, Gonçalo R., Boehnke, Michael, Kathiresan, Sekar·2010·Nature

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.

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Authors
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., Johansen, C. T., Fouchier, S. W., Isaacs, A., Peloso, G. M., Barbalic, M., Ricketts, S. L., Bis, J. C., Aulchenko, Y. S., Thorleifsson, G., Feitosa, M. F., Chambers, J., Orho-Melander, M., Melander, O., Johnson, T., Li, X., Guo, X., Li, M., Shin Cho, Y., Jin Go, M., Jin Kim, Y., Lee, J.-Y., Park, T., Kim, K., Sim, X., Twee-Hee Ong, R., Croteau-Chonka, D. C., Lange, L. A., Smith, J. D., Song, K., Hua Zhao, J., Yuan, X., Luan, J., Lamina, C., Ziegler, A., Zhang, W., Zee, R. Y. L., Wright, A. F., Witteman, J. C. M., Wilson, J. F., Willemsen, G., Wichmann, H.-E., Whitfield, J. B., Waterworth, D. M., Wareham, N. J., Waeber, G., Vollenweider, P., Voight, B. F., Vitart, V., Uitterlinden, A. G., Uda, M., Tuomilehto, J., Thompson, J. R., Tanaka, T., Surakka, I., Stringham, H. M., Spector, T. D., Soranzo, N., Smit, J. H., Sinisalo, J., Silander, K., Sijbrands, E. J. G., Scuteri, A., Scott, J., Schlessinger, D., Sanna, S., Salomaa, V., Saharinen, J., Sabatti, C., Ruokonen, A., Rudan, I., Rose, L. M., Roberts, R., Rieder, M., Psaty, B. M., Pramstaller, P. P., Pichler, I., Perola, M., Penninx, B. W. J. H., Pedersen, N. L., Pattaro, C., Parker, A. N., Pare, G., Oostra, B. A., O’Donnell, C. J., Nieminen, M. S., Nickerson, D. A., Montgomery, G. W., Meitinger, T., McPherson, R., McCarthy, M. I., McArdle, W., Masson, D., Martin, N. G., Marroni, F., Mangino, M., Magnusson, P. K. E., Lucas, G., Luben, R., Loos, R. J. F., Lokki, M.-L., Lettre, G., Langenberg, C., Launer, L. J., Lakatta, E. G., Laaksonen, R., Kyvik, K. O., Kronenberg, F., König, I. R., Khaw, K.-T., Kaprio, J., Kaplan, L. M., Johansson, Å., Jarvelin, M.-R., Cecile J. W. Janssens, A., Ingelsson, E., Igl, W., Kees Hovingh, G., Hottenga, J.-J., Hofman, A., Hicks, A. A., Hengstenberg, C., Heid, I. M., Hayward, C., Havulinna, A. S., Hastie, N. D., Harris, T. B., Haritunians, T., Hall, A. S., Gyllensten, U., Guiducci, C., Groop, L. C., Gonzalez, E., Gieger, C., Freimer, N. B., Ferrucci, L., Erdmann, J., Elliott, P., Ejebe, K. G., Döring, A., Dominiczak, A. F., Demissie, S., Deloukas, P., de Geus, E. J. C., de Faire, U., Crawford, G., Collins, F. S., Chen, Y.-D. I., Caulfield, M. J., Campbell, H., Burtt, N. P., Bonnycastle, L. L., Boomsma, D. I., Boekholdt, S. M., Bergman, R. N., Barroso, I., Bandinelli, S., Ballantyne, C. M., Assimes, T. L., Quertermous, T., Altshuler, D., Seielstad, M., Wong, T. Y., Tai, E.-S., Feranil, A. B., Kuzawa, C. W., Adair, L. S., Taylor Jr, H. A., Borecki, I. B., Gabriel, S. B., Wilson, J. G., Holm, H., Thorsteinsdottir, U., Gudnason, V., Krauss, R. M., Mohlke, K. L., Ordovas, J. M., Munroe, P. B., Kooner, J. S., Tall, A. R., Hegele, R. A., Kastelein, J. J. P., Schadt, E. E., Rotter, J. I., Boerwinkle, E., Strachan, D. P., Mooser, V., Stefansson, K., Reilly, M. P., Samani, N. J., Schunkert, H., Cupples, L. A., Sandhu, M. S., Ridker, P. M., Rader, D. J., van Duijn, C. M., Peltonen, L., Abecasis, G. R., Boehnke, M., & Kathiresan, S.
Affiliations
  • University of Michigan (US)
  • Broad Institute (US)
  • University of Iceland (IS)
  • University of Pennsylvania (US)
  • Columbia University (US)
  • University of Helsinki (FI)
  • Brigham and Women's Hospital (US)
  • Western University (CA)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Erasmus MC (NL)
  • Boston University (US)
  • University of Cambridge (GB)
  • University of Washington (US)
  • Washington University in St. Louis (US)
  • Imperial College London (GB)
  • Lund University (SE)
  • Queen Mary University of London (GB)
  • Cedars-Sinai Medical Center (US)
  • Korea National Institute of Health (KR)
  • Seoul National University (KR)
  • Sookmyung Women's University (KR)
  • National University of Singapore (SG)
  • University of North Carolina at Chapel Hill (US)
  • GlaxoSmithKline (United States) (US)
  • Addenbrooke's Hospital (GB)
  • Innsbruck Medical University (AT)
  • University of Lübeck (DE)
  • Institute of Genetics and Cancer (GB)
  • University of Edinburgh (GB)
  • Vrije Universiteit Amsterdam (NL)
  • Helmholtz Munich (DE)
  • QIMR Berghofer Medical Research Institute (AU)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • Institute of Genetic and Biomedical Research (IT)
  • Finnish Institute for Health and Welfare (FI)
  • University of Leicester (GB)
  • National Institutes of Health (US)
  • King's College London (GB)
  • Amsterdam Neuroscience (NL)
  • Helsinki University Hospital (FI)
  • Istituti di Ricovero e Cura a Carattere Scientifico (IT)
  • Hammersmith Hospital (GB)
  • National Institute on Aging (US)
  • Stanford University (US)
  • University of Oulu (FI)
  • University of Ottawa (CA)
  • Group Health Cooperative (US)
  • Eurac Research (IT)
  • Karolinska Institutet (SE)
  • Amgen (United States) (US)
  • Harvard University (US)
  • TUM Klinikum (DE)
  • Centre for Human Genetics (GB)
  • University of Bristol (GB)
  • Istituto di Genomica Applicata (IT)
  • Municipal Institute for Medical Research (ES)
  • Montreal Heart Institute (CA)
  • Tampere University Hospital (FI)
  • University of Southern Denmark (DK)
  • Massachusetts General Hospital (US)
  • Uppsala University (SE)
  • University of Regensburg (DE)
  • University of Leeds (GB)
  • University of California, Los Angeles (US)
  • University of Glasgow (GB)
  • University of Southern California (US)
  • Wellcome Sanger Institute (GB)
  • Azienda Sanitaria di Firenze (IT)
  • Baylor College of Medicine (US)
  • Stanford Medicine (US)
  • Genome Institute of Singapore (SG)
  • University of San Carlos (PH)
  • Northwestern University (US)
  • University of Mississippi Medical Center (US)
  • Sage Bionetworks (US)
  • The University of Texas Health Science Center at Houston (US)
  • St George's, University of London (GB)
Corresponding author
Kathiresan, Sekar
ORCID
Venue
Nature
Published
2010-08
Volume
466
Issue
7307
Pages
707-713
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2115801316
Cited by
3,487
References
20
Citations by year
2026: 69 · 2025: 82 · 2024: 111 · 2023: 151 · 2022: 180 · 2021: 178 · 2020: 170 · 2019: 214 · 2018: 257 · 2017: 249 · 2016: 272 · 2015: 322 · 2014: 325 · 2013: 297 · 2012: 308
FWCI
126.99
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion)
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  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • National University of Singapore (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
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  • UNC Libraries
Funders
  • GlaxoSmithKline
  • Wellcome Trust (068545/Z/02), 077016/Z/05/Z, 079895, ­076113/B/04/Z)
  • British Heart Foundation (PG/08/094/26019, SP/08/005/25115, PG/02/128, RG/07/005/23633, PG/08/094)
  • National Institutes of Health (2r24hd050924-06, n01hc085082-026, n01hc085081-021, 5r01dk068336-03, n01hc045133-001, n01ag12100-57-0-2, n01hc085079-024, n01hc015103-009, n01hc085084-005, n01hc55021-47-0-1, n01hc085085-011, n01hc085083-027, n01hc55020-39-0-0, n01hc085080-026, n01hc55016-37-0-0, n01hc055022-024, n01hg065403-000, n01hc085086-022, 5r01hl087700-03, n01hc55019-35-0-1, 6r01hl087679-03, 5k99hl094535-02, n01hc55018-38-0-1, n01hc25195-41-0-1, 5r01hl088215-04, 5p20rr020649-03, 6u54rr020278-06, n01hc55222-0-0-0, n01hc075150-004, n01hc035129-010, n01hc55015-48-0-1)
  • U.S. Public Health Service (HHSN 268200625226C)
  • Medical Research Council (MC_qA137934)
  • National Institute on Aging (N01-AG12100)
  • National Heart, Lung, and Blood Institute (N01-HC-85081, N01HC85085, R01HL080467, N01-HC55022, N01HC-85083, N01-HC-55018, 5R01 HL087679-02, N01HC15103, 5R01 HL08770003, N01 HC 55020, N01‐HC25195, N01 HC 55019, RC2HL101864, N01HC85082, N01HC‐75150, N01 HC85086, R01HL087676, R01HL087652, R01HL089309, N01HC85080, N02- HL-64278, N01 HC55222, U01HL069757, N01‐HC‐45133, ­N01-HC55016, R01HL087641, R01HL059367, R01HL054776, U01HL080295, 5-R01-HL-08821502, K99HL098364, R01HL085144, K23HL004381, K99-HL094535, N01‐HC‐55015, RC1HL099634, N01-HC55021, RC1HL099793, R01HL089650, RC2HL102419, T32HL007208, R01HL086694, N01-HC85079, ­N01-HC85084, N01HC35129)
  • National Human Genome Research Institute (Z01HG000024, U01HG004402, N01 HG-65403, T32HG000040)
  • National Cancer Institute (R01CA047988)
  • National Institute of General Medical Sciences (T32GM007092)
  • Fogarty International Center (R01TW005596)
  • National Institute of Diabetes and Digestive and Kidney Diseases (5R01 DK06833603, R01DK078150, R01DK072193, U01DK062370, R01DK075681, U01DK062418, DK-062370, P30DK063491, P30DK056350)
  • National Institute of Environmental Health Sciences (P30ES010126)
  • National Center for Research Resources (U54-RR020278, UL1RR025005, RR20649, M01RR000425)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24 HD-050924)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
plasma lipids, genetic association, cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, coronary artery disease, lipoprotein metabolism, single nucleotide polymorphisms, CYP7A1, NPC1L1, scavenger receptor class B type I, GALNT2, PPP1R3B, cross-population validation, East Asians, South Asians, African Americans, mouse model
MeSH terms
Polypeptide N-acetylgalactosaminyltransferase, Animals, Black or African American, Coronary Artery Disease, Europe, Female, Genotype, Humans, Lipids, Cholesterol, HDL, Cholesterol, LDL, Liver, Male, Phenotype, Triglycerides, Reproducibility of Results, N-Acetylgalactosaminyltransferases, Polymorphism, Single Nucleotide, White People, Asian People, Lipid Metabolism, Mice, Protein Phosphatase 1, Genome-Wide Association Study, Genetic Loci

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