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Abstract Background This study aims to develop a model for simultaneously assessing genetic and epigenetic contributions to plasma lipid levels. Methods The 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 (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 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. Results A 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. Conclusions Our 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.
Takeuchi et al. (Tue,) studied this question.