Familial hypercholesterolaemia

Abstract

Familial hypercholesterolaemia is a common inherited disorder characterized by abnormally elevated serum levels of low-density lipoprotein (LDL) cholesterol from birth, which in time can lead to cardiovascular disease (CVD). Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor, although mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently. Several sets of diagnostic criteria for familial hypercholesterolaemia are available; common diagnostic features are an elevated LDL cholesterol level and a family history of hypercholesterolaemia or (premature) CVD. DNA-based methods to identify the underlying genetic defect are desirable but not essential for diagnosis. Cascade screening can contribute to early diagnosis of the disease in family members of an affected individual, which is crucial because familial hypercholesterolaemia can be asymptomatic for decades. Clinical severity depends on the nature of the gene that harbours the causative mutation, among other factors, and is further modulated by the type of mutation. Lifelong LDL cholesterol-lowering treatment substantially improves CVD-free survival and longevity. Statins are the first-line therapy, but additional drugs, such as ezetimibe, bile acid sequestrants, PCSK9 inhibitors and other emerging therapies, are often required.

Characterization of LDLR rs5925 and PCSK9 rs505151 genetic variants frequencies in healthy subjects from northern Chile: Influence on plasma lipid levels

“…2 Most of these CVD are associated with increased plasma levels of low-density lipoprotein cholesterol (LDL-C). 6 In this study, we evaluated LDLR rs5925 (1959C > T or AvaII) genetic variant, previously reported to be associated with increased total cholesterol (TC) and LDL-C in Chinese, Brazilian, Hispanic, and non-Hispanic white individuals. This receptor is a 160-KDa transmembrane glycoprotein, ubiquitously distributed and encoded by LDLR gene located in chromosome 19, which spans 45 Kb and contains 18 exons encoding for six functional domains in the mature protein.…”

“…4,5 LDLR gene mutations represent the main genetic cause of familial hypercholesterolemia suggesting a mechanism involving genetic factors. 6 In this study, we evaluated LDLR rs5925 (1959C > T or AvaII) genetic variant, previously reported to be associated with increased total cholesterol (TC) and LDL-C in Chinese, Brazilian, Hispanic, and non-Hispanic white individuals. [7][8][9] Besides, this genetic variant was strongly associated with differences on plasma lipid levels in subjects with high risk of CVD and lower response to fluvastatin treatment.…”

Further options for treating lipids in people with diabetes: targeting LDL‐cholesterol and beyond

“…The discovery that some people with familial hypercholesterolaemia did not have mutations in the LDL-receptor or its apolipoprotein B 100 ligand but had activating mutations in proprotein convertase subtilisin kexin-9 (PCSK-9), a protein involved in controlling LDL receptor expression, induced interest in this molecule as a drug target [22]. Furthermore, inactivating mutations in PCSK-9 were associated with lower LDL-cholesterol, higher LDL receptor expression and reduced rates of CVD in epidemiological studies.…”

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

“…1 The severity of the HoFH phenotype and its ominous consequences correlate with LDL-C levels. The latter are influenced primarily by the type of familial hypercholesterolemia (FH)-causing molecular defect.…”