Research Project:
NUTRITION, CARDIOVASCULAR HEALTH, AND GENOMICS
Location: Human Nutrition Research Center on Aging
Title: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
Authors
![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Kathiresan, Sekar - MASS GENERAL HOSP, BOSTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Melander, Olle - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Guiducci, Candance - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Surti, Aarti - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Burtt, Noel - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Rieder, Mark - HOSP MALMO, SWEDEN | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Cooper, Gregory - HOSP MALMO, SWEDEN | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Roos, Charlotta - MASS GENERAL HOSP, BOSTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Voight, Benjamin - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Havulinna, Aki - UNIV OF WASHINGTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Wahlstrand, Bjorn - SAHLGRENSKA UNIV HOSPITAL | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Hedner, Thomas - SAHLGRENSKA UNIV HOSPITAL | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Corella, Dolores - SAHLGRENSKA UNIV HOSPITAL | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Tai, E - SINGAPORE GENERAL HOPS | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) |
Ordovas, Jose
| ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Berglund, Goran - UNIV OF WASHINGTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Vartiainen, Erkki - UNIV OF WASHINGTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Jousilahti, Pekka - UNIV OF WASHINGTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Hedblad, Bo - MASS GENERAL HOSP, BOSTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Taskinen, Marja-Ritta - UNIV OF HELSINKI, FINLAND | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Newton-Cheh, Christopher - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Salomaa, Veikko - UNIV OF WASHINGTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Peltonen, Leena - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Groop, Leif - MASS GENERAL HOSP, BOSTON | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Altshuler, David - BROAD INST, MIT & HARVARD | ![item](https://webarchive.library.unt.edu/eot2008/20090514205800im_/http://www.ars.usda.gov/incme/images/bullet.gif) | Orho-Melander, Marju - MASS GENERAL HOSP, BOSTON |
Submitted to: Nature Genetics
Publication Type:
Peer Reviewed Journal
Publication Acceptance Date: January 13, 2008
Publication Date: February 1, 2008
Publisher's URL: http://www.nature.com/ng/journal/v40/n2/abs/ng.75.html
Citation: Kathiresan, S., Melander, O., Guiducci, C., Surti, A., Burtt, N.P., Rieder, M.J., Cooper, G.M., Roos, C., Voight, B.F., Havulinna, A.S., Wahlstrand, B., Hedner, T., Corella, D., Tai, E.S., Ordovas, J.M., Berglund, G., Vartiainen, E., Jousilahti, P., Hedblad, B., Taskinen, M., Newton-Cheh, C., Salomaa, V., Peltonen, L., Groop, L., Altshuler, D.M., Orho-Melander, M. 2008. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nature Genetics. 40(2):189-197.
Interpretive Summary: Blood low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol concentrations are known risk factors for cardiovascular disease and blood triglycerides reflect key metabolic processes including sensitivity to insulin and therefore risk for metabolic syndrome and diabetes. Blood lipoprotein and lipid concentrations are heritable and most of the heritability of blood lipoproteins and lipids remains unexplained by known genes and gene variants. We have thoroughly analyzed the genomes of over 8816 subjects and replicated promising findings in up to 18,554 additional indidviduals. Our data reveal that common single nucleotide polymorphisms (SNPs) at six new genes are reproducibly associated with LDL cholesterol, HDL cholesterol, and/or triglycerides. These findings represent a major, new advance on our knowledge of genetic factors involved in cardiovascular disease risk. Understanding their molecular, cellular, and clinical consequences may inform disease prevention and therapy.
Technical Abstract: Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease and blood triglycerides reflect key metabolic processes including sensitivity to insulin. Blood lipoprotein and lipid concentrations are heritable. To date, the identification of causal genes for Mendelian dyslipidemic syndromes has transformed our understanding of lipoprotein metabolism and the treatment of cardiovascular disease. Nonetheless, most of the heritability of blood lipoproteins and lipids remains unexplained by known genes and gene variants. Using genome-wide association data from three studies (n=8816) and targeted replication association analyses in up to 18,554 independent participants, we show that common single nucleotide polymorphisms (SNPs) at six new loci are reproducibly associated with LDL cholesterol, HDL cholesterol, and/or triglycerides (P<5x10-8 for each new locus). Of the six novel chromosomal regions, two were associated with a single lipoprotein or lipid trait: 1p13 (near CELSR2/PSRC1/SORT1) with LDL cholesterol and 1p31 (near ANGPTL3) with triglycerides. Three loci were related to two lipoprotein or lipid traits: 19p13 (near CILP2/PBX4) with LDL cholesterol and triglycerides and both 1q42 (in GALNT2) and 7q11 (near TBL2/MLXIPL) with HDL cholesterol and triglycerides. One locus, 8q24 (near TRIB1), affected all three lipoprotein or lipid traits. At 1p13, the LDL-associated SNP was also strongly correlated with liver transcript levels of SORT1 (P=2x10-26) as well as two other neighboring genes, suggesting that this SNP may act as a regional regulator of gene expression. Common polymorphisms at six novel loci have distinct effects on lipoprotein and lipid concentrations; understanding their molecular, cellular, and clinical consequences may inform therapy and clinical care.
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