Simultaneous Assessment of Genetic and Epigenetic Contributions to the Plasma Lipid Levels with Respect to Cardiovascular Risk.

This study aimed to develop a model to simultaneously assess the genetic and epigenetic contributions to plasma lipids. The study used two cardiovascular risk groups: individuals with high low-density lipoprotein cholesterol (LDL-C) levels (N = 296) and coronary artery disease (CAD) (N = 315), in contrast to the reference (max N = 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 the epigenetic profile based on the DNA methylation levels at the 17 CpG sites. The relationship between each lipid level and these variables was analyzed using regression and quantile models. Functionally significant rare variants were identified more frequently in patients with high LDL-C or CAD than in the general Japanese population (3.8% vs. 2.3%). For LDL-C, the model incorporating both PRSLDL-C (plus rare variants) and MRSLDL-C showed a higher correlation between the predicted and measured values (r = 0.272, P = 3.7×10-12) than those using PRSLDL-C alone (r = 0.106, P = 0.008) and PRSLDL-C plus rare variants (r = 0.263, P = 1.9×10-11). 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 lipid traits, as well as LDL-C. Our results provide a proof-of-concept that assesses the relative contribution of genetic predisposition and DNA methylation levels, which may help individuals refine their dyslipidemia treatment.