Epipolymorphisms within lipoprotein genes contribute independently to plasma lipid levels in familial hypercholesterolemia

• Published in: Epigenetics Vol. 9; no. 5; pp. 718 - 729
• Main Authors: Guay, Simon-Pierre, Brisson, Diane, Lamarche, Benoit, Gaudet, Daniel, Bouchard, Luigi
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.05.2014; Landes Bioscience
• Subjects: Adult; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - blood; ATP-Binding Cassette Transporters - genetics; candidate genes; Cholesterol, HDL - blood; Cholesterol, LDL - blood; coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - complications; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Genetic Loci; Humans; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - complications; Hyperlipoproteinemia Type II - genetics; Lipase - blood; Lipase - genetics; Lipoproteins - blood; Lipoproteins - genetics; Male; Middle Aged; missing heritability; Phospholipid Transfer Proteins - blood; Phospholipid Transfer Proteins - genetics; plasma lipid levels; Polymorphism, Genetic; Research Paper; Scavenger Receptors, Class B - blood; Scavenger Receptors, Class B - genetics; Sex Factors; Triglycerides - blood; coronary artery disease; DNA methylation; missing heritability; candidate genes; plasma lipid levels
• ISSN: 1559-2294; 1559-2308; 1559-2308
• DOI: 10.4161/epi.27981

Gene polymorphisms associated so far with plasma lipid concentrations explain only a fraction of their heritability, which can reach up to 60%. Recent studies suggest that epigenetic modifications (DNA methylation) could contribute to explain part of this missing heritability. We therefore assessed whether the DNA methylation of key lipoprotein metabolism genes is associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels in patients with familial hypercholesterolemia (FH). Untreated FH patients (61 men and 37 women) were recruited for the measurement of blood DNA methylation levels at the ABCG1, LIPC, PLTP and SCARB1 gene loci using bisulfite pyrosequencing. ABCG1, LIPC and PLTP DNA methylation was significantly associated with HDL-C, LDL-C and triglyceride levels in a sex-specific manner (all P < 0.05). FH subjects with previous history of coronary artery disease (CAD) had higher LIPC DNA methylation levels compared with FH subjects without CAD (P = 0.02). Sex-specific multivariable linear regression models showed that new and previously reported epipolymorphisms (ABCG1-CpGC3, LIPC-CpGA2, mean PLTP-CpGC, LPL-CpGA3, CETP-CpGA2, and CETP-CpGB2) significantly contribute to variations in plasma lipid levels (all P < 0.001 in men and P < 0.02 in women), independently of traditional predictors such as age, waist circumference, blood pressure, fasting plasma lipids and glucose levels. These results suggest that epigenetic perturbations of key lipoprotein metabolism genes are associated with plasma lipid levels, contribute to the interindividual variability and might partially explain the missing heritability of plasma lipid levels, at least in FH.