This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chasman, D. I. Articles by Ridker, P. M Search for Related Content PubMed Articles by Chasman, D. I. Articles by Ridker, P. M Related Collections Genomics Genetics of cardiovascular disease Lipid and lipoprotein metabolism

Original Articles

Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication

Daniel I. Chasman, PhD^*; Guillaume Paré, MD, MS^*; Robert Y.L. Zee, PhD, MPH; Alex N. Parker, PhD; Nancy R. Cook, ScD; Julie E. Buring, ScD; David J. Kwiatkowski, MD, PhD; Lynda M. Rose, MS; Joshua D. Smith, BS; Paul T. Williams, PhD; Mark J. Rieder, PhD; Jerome I. Rotter, MD; Deborah A. Nickerson, PhD; Ronald M. Krauss, MD; Joseph P. Miletich, MD and Paul M Ridker, MD, MPH

From the Center for Cardiovascular Disease Prevention (D.I.C., G.P., R.Y.L.Z., N.R.C., J.E.B., L.M.R., P.M.R.) and Donald W. Reynolds Center for Cardiovascular Research (D.I.C., G.P., R.Y.L.Z., N.R.C., D.J.K., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Amgen, Inc, Cambridge, Mass (A.N.P., J.M.P.); Department of Genome Sciences, University of Washington, Seattle, Wash (J.D.S., M.J.R., D.A.N.); Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, Calif (P.T.W., R.M.K.); Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, Calif (J.I.R.); and Children’s Hospital Oakland Research Institute, Oakland, Calif (R.M.K.).

Correspondence to Daniel I. Chasman, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail dchasman{at}rics.bwh.harvard.edu

Received February 13, 2008; accepted June 23, 2008.

Background— Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.

Methods and Results— We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein (Apo) A1, and ApoB. Genome-wide associations (P<5x10^–8) were found at the PCSK9 gene, the APOB gene, the LPL gene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus. In addition, genome-wide associations with triglycerides at the GCKR gene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the SORT1 gene. Below genome-wide significance, our study provides confirmatory evidence for associations at 5 novel loci with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB.

Conclusion— Genome-wide associations at the GCKR gene and near the SORT1 gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.

Key Words: lipoproteins • lipids • cardiovascular diseases • population genetics

---

 

CLINICAL PERSPECTIVE

*Drs Chasman and Paré contributed equally.

Guest Editor for this article was Donna K. Arnett, PhD.

The online Data Supplement can be found with this article at http://circgenetics.ahajournals.org/cgi/content/full/1/1/21/DC1.

This article has been cited by other articles:

				M. B. Lanktree, S. S. Anand, S. Yusuf, R. A. Hegele, and the SHARE Investigators Replication of genetic associations with plasma lipoprotein traits in a multiethnic sample J. Lipid Res., July 1, 2009; 50(7): 1487 - 1496. [Abstract] [Full Text] [PDF]

				R. McPherson A Gene-Centric Approach to Elucidating Cardiovascular Risk Circ Cardiovasc Genet, February 1, 2009; 2(1): 3 - 6. [Full Text] [PDF]

				P. M. Ridker, G. Pare, A. N. Parker, R. Y.L. Zee, J. P. Miletich, and D. I. Chasman Polymorphism in the CETP Gene Region, HDL Cholesterol, and Risk of Future Myocardial Infarction: Genomewide Analysis Among 18 245 Initially Healthy Women From the Women's Genome Health Study Circ Cardiovasc Genet, February 1, 2009; 2(1): 26 - 33. [Abstract] [Full Text] [PDF]

				D. I. Chasman, G. Pare, and P. M Ridker Population-Based Genomewide Genetic Analysis of Common Clinical Chemistry Analytes Clin. Chem., January 1, 2009; 55(1): 39 - 51. [Abstract] [Full Text] [PDF]

				A. C. Edmondson and D. J. Rader Genome-Wide Approaches to Finding Novel Genes for Lipid Traits: The Start of a Long Road Circ Cardiovasc Genet, October 1, 2008; 1(1): 3 - 6. [Full Text] [PDF]