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LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Reporter: Aviva Lev-Ari, PhD, RN

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

Author Affiliations

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@rics.bwh.harvard.edu

Abstract

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<5×10⁻⁸) were found at the PCSK9 gene, the APOB gene, the LPLgene, 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 GCKRgene 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 SORT1gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.

 SOURCE:

Circulation: Cardiovascular Genetics.2008; 1: 21-30

doi: 10.1161/ CIRCGENETICS.108.773168