Genes Potentially Associated with Familial Hypercholesterolemia.

Svetlana Mikhailova,Elena Shakhtshneider,Olga Timoshchenko,Dinara Ivanoshchuk

doi:10.3390/biom9120807

Abstract

This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%–40% of the cases. The genes STAP1 (signal transducing adaptor family member 1), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), LIPA (lipase A, lysosomal acid type), ABCG5 (ATP binding cassette subfamily G member 5), ABCG8 (ATP binding cassette subfamily G member 8), and PNPLA5 (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia.

Highlights

Familial hypercholesterolemia (FH) is a monogenic disease with mostly autosomal dominant inheritance and is characterized by substantial elevation of the blood level of cholesterol associated with low-density lipoproteins (LDL-C) and by the early development and progression of atherosclerosis [1]
Among Hungarian patients with cardiovascular diseases, the frequency of carriers of genotype Tyr/Tyr of substitution Y54Cys in the ABCG8 gene is lower among males younger than 50 with myocardial infarction, whereas the level of cholesterol is lower in Tyr/Tyr carriers than in the carriers of genotypes Tyr/Cys and Cys/Cys in a control sample [97]
In 2018, the Familial Hypercholesterolemia Foundation initiated an assessment of the usefulness of genetic testing for FH and invited an international expert group

Summary

Introduction

Familial hypercholesterolemia (FH) is a monogenic disease with mostly autosomal dominant inheritance and is characterized by substantial elevation of the blood level of cholesterol associated with low-density lipoproteins (LDL-C) and by the early development and progression of atherosclerosis [1]. We discuss six genes STAP1 (signal transducing adaptor family member 1), CYP7A1. One more carrier of p.Glu97Asp and three additional mutations, p.Leu69Ser (c.206T>C, rs938523789), p.Ile71Thr (c.212T>C, rs141647940), and p.Asp207Asn (c.619G>A, rs146545610), were identified in the coding regions of the STAP1 gene in 400 unrelated probands with FH and without mutations in known FH-associated genes using a sequencing analysis. During a screening of patients with elevated LDL-C in Spain, a mutation (c.291G>C, p.Glu97Asp) in the STAP1 gene was found in the family of one patient [31]. These data show that substitutions in the STAP1 gene most likely are not the cause of definite FH, and this gene’s role in the regulation of lipid metabolism requires further research

CYP7A1

ABCG5 and ABCG8

PNPLA5

Findings

Conclusions