Simultaneous assessment of genetic and epigenetic contributions to plasma lipid levels with respect to cardiovascular risk

Abstract

AbstractBackgroundThis study aims to develop a model for simultaneously assessing genetic and epigenetic contributions to plasma lipid levels.MethodsThe predictive model was developed using two cardiovascular risk groups, i.e., individuals with high low-density lipoprotein cholesterol (LDL-C) levels (≥160 mg/dl,N= 296) and coronary artery disease (CAD) (N= 315), in contrast to reference (maxN= 3,801) and non-CAD individuals (N= 164). For genetic predisposition, rare pathological variants in five target genes related to familial hypercholesterolemia (FH) were screened, while common variants were characterized to calculate a polygenic risk score (PRS). The methylation risk score (MRS) was also calculated for epigenetic profiles based on DNA methylation levels at 13 CpG sites. A relationship between these variables and lipid levels was analyzed in regression and quantile models.ResultsA total of 17 rare FH-related gene variants were identified in patients with high LDL-C or CAD, significantly more prevalent than in the general Japanese population (2.8% vs. 0.2%,P<1×10−15). For the rare variants plus PRS, the predictability of individual LDL-C increased (correlation coefficient between predicted and measured values,r= 0.261,P= 1.7×10−11) compared to PRS alone (r= 0.151,P= 1.2×10−4). PRS and MRS had the most significant impact on high-density lipoprotein cholesterol and triglycerides, respectively. The two risk scores had additive effects on these traits.ConclusionsOur results provide proof-of-concept that assessing the relative contribution of genetic predisposition and DNA methylation levels (reflecting past environmental exposures) may help individuals refine their dyslipidemia treatment.