RESUMO
High-density lipoproteins cholesterol (HDL-C) level, a strong coronary artery disease (CAD) clinical biomarker, shows significant interindividual variability. However, the molecular mechanisms involved remain mostly unknown. ATP-binding cassette A1 (ABCA1) catalyzes the cholesterol transfer from peripheral cells to nascent HDL particles. Recently, a differentially methylation region was identified in ABCA1 gene promoter locus, near the first exon. Therefore, we hypothesized that DNA methylation changes at ABCA1 gene locus is one of the molecular mechanisms involved in HDL-C interindividual variability. The study was conducted in familial hypercholesterolemia (FH), a monogenic disorder associated with a high risk of CAD . Ninety-seven FH patients (all p.W66G for the LDLR gene mutation and not under lipid-lowering treatment) were recruited and finely phenotyped for DNA methylation analyses at ABCA1 gene locus. ABCA1 DNA methylation levels were found negatively correlated with circulating HDL-C (r = -0.20; p = 0.05), HDL2-phospholipid levels (r = -0.43; p = 0.04), and with a trend for association with HDL peak particle size (r = -0.38; p = 0.08). ABCA1 DNA methylation levels were also found associated with prior history of CAD (CAD = 40.2% vs. without CAD = 34.3%; p = 0.003). These results suggest that epigenetic changes within the ABCA1 gene promoter contribute to the interindividual variability in plasma HDL-C concentrations and are associated with CAD expression. These findings could change our understanding of the molecular mechanisms involved in the pathophysiological processes leading to CAD.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , HDL-Colesterol/metabolismo , Doença da Artéria Coronariana/genética , Metilação de DNA , Hiperlipoproteinemia Tipo II/genética , Regiões Promotoras Genéticas , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , HDL-Colesterol/sangue , HDL-Colesterol/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Epigênese Genética , Éxons , Feminino , Loci Gênicos , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Motivos de Nucleotídeos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/sangue , Receptores de LDL/genética , Receptores de LDL/metabolismo , Fatores de Risco , Adulto JovemRESUMO
AIM: 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. MATERIALS & METHODS: 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 TNNT1 gene was replicated in a cohort of 276 FH subjects using pyrosequencing. RESULTS: 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. TNNT1 DNA methylation levels were positively correlated with mean HDL particle size, HDL-phospholipid, HDL-apolipoprotein AI, HDL-C and TNNT1 expression levels. CONCLUSION: These results suggest that epigenome-wide changes account for interindividual variations in HDL particle metabolism and that TNNT1 is a new candidate gene for dyslipidemia.