Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease

Abstract

This article is available online at http://www.jlr.org M. E. Brousseau. Coronary heart disease (CHD) is a major cause of death and disability in our society, resulting in approximately 450,000 deaths per year in the United States (2009 Heart and Stroke Statistical Update). Numerous population studies have shown that a strong inverse relationship exists between plasma high density lipoprotein cholesterol (HDL-C) concentrations and CHD risk ( 1-4 ). Approximately 50% of men with CHD have a low level of HDL-C, and not elevated low density lipoprotein cholesterol (LDL-C), as their primary lipid abnormality ( 5 ). In fact, a study in men has shown that a low level of HDL-C better distinguishes CHD status than a high level of LDL-C ( 6 ).Abstract A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and infl ammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefi ts of HDL-raising with gemfi brozil in men with low HDL-C ( ≤ 40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) signifi cantly associated with case status were identifi ed in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel fi ndings of this study are the identifi cation of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA , and the observation that genetic variation in SELP may infl uence CHD risk through its effects on HDL. -Peloso, G.

Goat liver X receptor α, molecular cloning, functional characterization and regulating fatty acid synthesis in epithelial cells of goat mammary glands

“…Cloning of full-length cDNA of the goat LXRα gene As a superfamily of ligand-activated transcription regulators, it is well known that the LXRα plays an important role in the transcriptional regulation of lipid homeostasis. Recently, LXRα was cloned from cattle (Sonstegard et al, 2002) and mice (Diez-Roux et al, 2011;Peloso et al, 2010). However, to date, the information concerning the role of LXRα in goats has been scarce.…”

Network-based Analysis of Genome Wide Association Data Provides Novel Candidate Genes for Lipid and Lipoprotein Traits

“…Many of our prioritized candidates for lipid traits are related to cardiovascular and coronary artery disease in the literature (40,42,45) (supplemental Table S3), providing a common sense measure of the usefulness of our raw data and methodology.…”

“…D, Median odds ratios of GO term enrichment as a measure of enrichment effect size. Network-based Analysis of Genome Wide Association Data rs11185660 has been associated with low HDL-C and coronary heart disease (40,41). TG and nonesterified fatty acid (NEFA) levels were increased in the livers and serum of cysthathionine-beta-synthase (CBS) knock out mice (41).…”

Modulated expression of genes associated with NO signal transduction contributes to the cholesterol-lowering effect of electro-acupuncture

“…We have addressed whether any of the differentially expressed genes identified overlap the previous studies. Because of the low amount of the differentially-expressed genes identified and the different output resulting from the different screening systems, only Apoa2, in which defects may result in Apoa2 deficiency and hypercholesterolemia (Peloso et al 2010), and 6 unannotated genes were reported by previous study (Tables 1, 2). Despite this, some genes, including Dhx32 and Rpl41 (Table 1), Furthermore and similar to the previous report, all of the annotated differentially-expressed genes are involved in metabolism, transport, immune response, signal transduction, cell cycle, etc.…”