Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

Abstract

This article is available online at http://www.jlr.orgCholesterol concentrations from lipoprotein fractions are some of the most commonly used clinical biomarkers of cardiovascular and metabolic disease risk ( 1 ). However, LDL cholesterol and HDL cholesterol concentrations do not account for all lipid-based CVD risk ( 1 ). In addition, the causal role of HDL cholesterol with CVD is debated ( 2 ). Thus, alternative lipid biomarkers of CVD are useful for gaining a more complete CVD risk profi le and for exploring the mechanisms that may underlie cardiovascular events.Within each lipoprotein fraction, the constituent particles are heterogeneous in their size and composition. The particles forming the VLDL, LDL, and HDL fractions may be further subdivided into subfractions based on their size, which partially refl ects the cholesterol content of the particle. Specifi c constellations of subfractions have been associated with insulin resistance (IR) and atherosclerosis ( 3-9 ).Currently, lipoprotein subfractions are limited in their clinical utility due to a lack of evidence that they con vey information on the likelihood of experiencing an adverse cardiovascular event over and above that of traditional anthropometric, lipid, and demographic risk factors. However, identifying the genetic factors associated with lipoprotein subfractions may provide a more thorough understanding of the pathways that regulate lipoprotein composition and metabolism and so shed light on the etiology of atherosclerosis and IR. Numerous genetic loci have been associated with lipoprotein subfractions at Abstract Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the fi rst systematic screen of the genome to determine associations between methylation status at ‫ف‬ 470,000 cytosine-guanine dinucleotide (CpG) sites in CD4 + T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identifi ed two CpGs, both in the carnitine palmitoyltransferase-1A ( CPT1A ) gene, which reached signifi cant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases ( P < 1.1 × 10 ؊ 7 in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10 ؊ 12 in the full sample). CPT1A is regulated by PPAR ␣ , a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this g...

Epigenetics of Lipid Phenotypes

“…Methylation at the top CPT1A locus explained 12% of TG variation in the discovery cohort (Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), CD4+ lymphocytes, n=991) and 6% in the replication cohort (Framingham Heart Study, whole blood, n=1261) [12]. Subsequent studies have replicated the observed association with lipids [7, 15, 16] and lipoprotein subfraction profiles [17], as well as linked CPT1A methylation with obesity traits [18, 19], metabolic syndrome [20], and hypertriglyceridemic waist [21] in diverse populations. Interestingly, CPT1A loci were also shown to be differentially methylated in Dutch Hunger Winter survivors exposed to famine in utero , associating with both birth weight and serum LDL cholesterol levels later in life [22] and providing a possible mechanism for the well-known adverse metabolic sequelae of prenatal malnutrition.…”

Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis

“…In humans, CPT1A deficiency causes hepatomegaly, hepatic steatosis, and metabolic perturbations (Bennett and Santani, 1993), while in rats, Cpt1a expression was shown to be down-regulated during steatosis in male rats consuming a high-fat diet (Xie et al , 2010), while a moderate overexpression of Cpt1a in obese male rats increased hepatic fatty acid β-oxidation and decreased hepatic triglyceride accumulation (Stefanovic-Racic et al , 2008). Cpt1a expression has been shown to be regulated by the binding of transcription factors (including C/EBPβ and SREBP1 (Attia et al , 2011; Thakran et al , 2013) in cell culture, as well as with altered DNA methylation in humans (Frazier-Wood et al , 2014; Irvin et al , 2014). However, despite the critical regulatory role of this gene in hepatic energy metabolism and lipid accumulation, and the proposed role of BPA exposure in NAFLD development, no studies have specifically assessed the gene’s potential epigenetic regulation in response to developmental BPA exposure.…”

Robust validation of methylation levels association at CPT1A locus with lipid plasma levels

“…In the current issue of the Journal , Frazier-Wood et al ( 8 ) reported the novel fi ndings of signifi cant negative correlations between methylation levels at two CpG sites in the CPT1A locus and plasma levels of VLDL and LDL. Methylation levels were assessed in CD4+ T-cells isolated from peripheral blood DNA using the HM450K array.…”