Epigenetic Hallmarks of Fetal Early Atherosclerotic Lesions in Humans

Importance: Although increasingly strong evidence suggests a role of maternal total cholesterol and low-density lipoprotein cholesterol (LDLC) levels during pregnancy as a risk factor for atherosclerotic disease in the offspring, the underlying mechanisms need to be clarified for future clinical applications. Objective: To test whether epigenetic signatures characterize early fetal atherogenesis associated with maternal hypercholesterolemia and to provide a quantitative estimate of the contribution of maternal cholesterol level to fetal lesion size. Design, Setting, and Participants: This autopsy study analyzed 78 human fetal aorta autopsy samples from the Division of Human Pathology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. Maternal levels of total cholesterol, LDLC, high-density lipoprotein cholesterol (HDLC), triglycerides, and glucose and body mass index (BMI) were determined during hospitalization owing to spontaneous fetal death. Data were collected and immediately processed and analyzed to prevent degradation from January 1, 2011, through November 30, 2016. Main Outcomes and Measurements: Results of DNA methylation and messenger RNA levels of the following genes involved in cholesterol metabolism were assessed: superoxide dismutase 2 (SOD2), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein 2 (SREBP2), liver X receptor α (LXRα), and adenosine triphosphate-binding cassette transporter 1 (ABCA1). Results: Among the 78 fetal samples included in the analysis (59% male; mean [SD] fetal age, 25 [3] weeks), maternal cholesterol level explained a significant proportion of the fetal aortic lesion variance in multivariate analysis (61%; P =.001) independently by the effect of levels of HDLC, triglycerides, and glucose and BMI. Moreover, maternal total cholesterol and LDLC levels were positively associated with methylation of SREBP2 in fetal aortas (Pearson correlation, 0.488 and 0.503, respectively), whereas in univariate analysis, they were inversely correlated with SREBP2 messenger RNA levels in fetal aortas (Pearson correlation, -0.534 and -0.671, respectively). Epivariations of genes controlling cholesterol metabolism in cholesterol-treated human aortic endothelial cells were also observed. Conclusions and Relevance: The present study provides a stringent quantitative estimate of the magnitude of the association of maternal cholesterol levels during pregnancy with fetal aortic lesions and reveals the epigenetic response of fetal aortic SREBP2 to maternal cholesterol level. The role of maternal cholesterol level during pregnancy and epigenetic signature in offspring in cardiovascular primary prevention warrants further long-term causal relationship studies