Dense Genotyping of Candidate Gene Loci Identifies Variants Associated With High-Density Lipoprotein Cholesterol
- 1 April 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation: Cardiovascular Genetics
- Vol. 4 (2), 145-155
- https://doi.org/10.1161/circgenetics.110.957563
Abstract
Background—: Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs. Methods and Results—: Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664 ) and provide evidence that suggests an association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4 ). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants. Conclusions—: Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.Keywords
This publication has 62 references indexed in Scilit:
- Biological, clinical and population relevance of 95 loci for blood lipidsNature, 2010
- Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChipAmerican Journal of Human Genetics, 2009
- Common variants at 30 loci contribute to polygenic dyslipidemiaNature Genetics, 2008
- Genome-wide association analysis of metabolic traits in a birth cohort from a founder populationNature Genetics, 2008
- Loci influencing lipid levels and coronary heart disease risk in 16 European population cohortsNature Genetics, 2008
- Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: A systematic in-depth reviewExperimental Gerontology, 2008
- Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humansNature Genetics, 2008
- Hepatic Proprotein Convertases Modulate HDL MetabolismCell Metabolism, 2007
- Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCATBiochemical Journal, 2007
- Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDLNature Genetics, 2007