title: Epipolymorphisms within lipoprotein genes contribute independently to plasma lipid levels in familial hypercholesterolemia.
abstract: 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.
authors: Department of Biochemistry; Université de Sherbrooke; Sherbrooke, QC Canada; ECOGENE-21 and Lipid Clinic; Chicoutimi Hospital; Saguenay, QC Canada.
authors: Simon-Pierre
authors: SP
authors: Guay
authors: ECOGENE-21 and Lipid Clinic; Chicoutimi Hospital; Saguenay, QC Canada; Department of Medicine; Université de Montréal; Montréal, QC Canada.
authors: Diane
authors: D
authors: Brisson
authors: Institute of Nutrition and Functional Foods; Université Laval; Québec, QC Canada.
authors: Benoit
authors: B
authors: Lamarche
authors: ECOGENE-21 and Lipid Clinic; Chicoutimi Hospital; Saguenay, QC Canada; Department of Medicine; Université de Montréal; Montréal, QC Canada.
authors: Daniel
authors: D
authors: Gaudet
authors: Department of Biochemistry; Université de Sherbrooke; Sherbrooke, QC Canada; ECOGENE-21 and Lipid Clinic; Chicoutimi Hospital; Saguenay, QC Canada.
authors: Luigi
authors: L
authors: Bouchard
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000097:blood / Q000235:genetics; D000328:Adult; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D056426:Genetic Loci; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000235:genetics*; D008049:Lipase / Q000097:blood / Q000235:genetics; D008074:Lipoproteins / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D049294:Phospholipid Transfer Proteins / Q000097:blood / Q000235:genetics; D011110:Polymorphism, Genetic; D051122:Scavenger Receptors, Class B / Q000097:blood / Q000235:genetics; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C504173:LIPC protein, human; D008074:Lipoproteins; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; D008049:Lipase
keywords: DNA methylation; candidate genes; coronary artery disease; missing heritability; plasma lipid levels