Epigenome-wide analysis in familial hypercholesterolemia identified new loci associated with high-density lipoprotein cholesterol concentration

This study aims to assess whether epigenetic changes may account for high-density lipoprotein cholesterol (HDL-C) level variability in familial hypercholesterolemia (FH), a recognized human model to study cardiovascular disease risk modulators. A genome-wide DNA methylation analysis (Infinium HumanMethylation27 BeadChip, Illumina) was performed on peripheral blood DNA samples obtained from men with FH with low (n = 10) or high (n = 11) HDL-C concentrations. The initial association with one of the top differentially methylated loci located in the promoter of the gene was replicated in a cohort of 276 FH subjects using pyrosequencing. According to the Ingenuity Pathway Analysis software, the HDL-C differentially methylated loci identified were significantly associated with pathways related to lipid metabolism and cardiovascular disease. DNA methylation levels were positively correlated with mean HDL particle size, HDL-phospholipid, HDL-apolipoprotein AI, HDL-C and expression levels. These results suggest that epigenome-wide changes account for interindividual variations in HDL particle metabolism and that is a new candidate gene for dyslipidemia.