Abstract
Cardiovascular disease (CVD) in heterozygous familial hypercholesterolemia (HeFH), the most frequent monogenic disorder of human metabolism, is largely driven by low-density lipoprotein (LDL) cholesterol concentrations. Since the CVD rate differs considerably in this population, beyond the lifetime LDL cholesterol vascular accumulation, other classical risk factors are involved in the high cardiovascular risk of HeFH. Among other lipoprotein disturbances, alterations in the phenotype and functionality of high-density lipoproteins (HDL) have been described in HeFH patients, contributing to the presence and severity of CVD. In fact, HDL are the first defensive barrier against the burden of high LDL cholesterol levels owing to their contribution to reverse cholesterol transport as well as their antioxidant and anti-inflammatory properties, among others. In this context, the present narrative review aimed to focus on quantitative and qualitative abnormalities in HDL particles in HeFH, encompassing metabolic, genetic and epigenetic aspects.
Highlights
Heterozygous familial hypercholesterolemia (HeFH), the most frequent human metabolism monogenic disorder caused by mutations in the genes encoding for the low-density lipoprotein (LDL) receptor [1], apolipoprotein (Apo) B-100 [2], proprotein convertase subtilisin/kexin-type 9 (PCSK9) [3] or Apo E [4], entails high LDL cholesterol concentrations, resulting in a high lifetime risk for cardiovascular disease (CVD)
Guay et al reported that DNA methylation levels at the ATP-binding cassette transporter A1 (ABCA1), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) gene promoter loci were associated with variations in high-density lipoprotein (HDL) size and cholesterol content, as well as a history of CVD in HeFH [68,69]
HDL cholesterol concentrations in FH and non-FH subjects, and with the prevalence of CVD in FH and non-FH men [71]. These results suggest that both epigenetic and genetic modifications at the 19q13.42 locus are associated with low HDL cholesterol levels and cardiovascular risk
Summary
Heterozygous familial hypercholesterolemia (HeFH), the most frequent human metabolism monogenic disorder caused by mutations in the genes encoding for the low-density lipoprotein (LDL) receptor [1], apolipoprotein (Apo) B-100 [2], proprotein convertase subtilisin/kexin-type 9 (PCSK9) [3] or Apo E [4], entails high LDL cholesterol concentrations, resulting in a high lifetime risk for cardiovascular disease (CVD). In this respect, a subject with a pathogenic FH mutation and LDL cholesterol > 190 mg/dL has a 22-fold increased risk of premature CVD compared with a mutation-negative subject with LDL cholesterol < 130 mg/dL [5]. The present narrative review aimed to focus on quantitative and qualitative abnormalities in HDL particles in HeFH, encompassing metabolic, genetic and epigenetic aspects
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