Abstract
Introduction
Familial hypercholesterolemia (FH) is the most common genetically inherited disease in the world, which leads to a significant increase in blood cholesterol and an increased risk of early atherosclerosis and, consequently, an increase in mortality from ischemic heart disease (IHD). The actual prevalence of genetic variants causing FH in every population remains unknown.
Purpose
To compare the frequency of mutations in patients with FH who underwent acute coronary syndrome (ACS) and patients with stable IHD.
Material and methods
We included 120 patients (male-79, female-41) who had a clinical diagnosis of FH based on the Dutch Lipid Clinic Network (DLCN) score and Simon Broome criteria. The men and women included in the study were ≤55 and ≤60 years of age, respectively. 40 of them were patients with ACS; the remaining 80 were patients with stable IHD. Genetic studies were performed using a multiple approach based on targeted Next Generation Sequencing (NGS) in the Health in code and the ReadSense laboratories.
Results
Variants of the three “classic” genes implicated in FH were detected in 46 patients (38,3%). The frequency of mutations was detected in 32.5% of cases, and in patients with stable IHD in 41.25% of cases (p=0.35). In the group of participants with stable IHD, a mutation in the LDLR gene was obtained in 85% of cases; mutations in the APOB, PCSK9 genes were detected in 15% of cases. The same rate of mutations in the APOB and LDLR genes (38.5% each) was detected in patients with ACS. One patient had a mutation in the PCSK9 gene. In two patients there were mutations at once in two genes responsible for the development of FH: in one case, mutations were determined in the APOB and LDLR genes, in the other - LDLR and PCSK9. All patients who carried variants of the studied genes were heterozygous.
Patients with clinically established FH had mutations in other genes involved in lipid metabolism, such as APOE, which turned to be mutant in 20 participants (16,6%). This variant defines the apoE4 isoform (also called ε4 allele), which is one of the three common genetic isoforms (apoE2, apoE3, and apoE4) of the APOE gene. It has been shown that the choice of apoE4 isoform have TC and LDL levels and increased risk of cardiovascular events related to atherosclerosis. Two patients had LPA mutations. This variant is a genetic polymorphism that has been previously published in association with elevated lipoprotein (a) (Lp(a)) levels and increased risk of IHD. Three patients were found to have ABCG8 mutations thought to be associated with sitosterolemia: two were pathogenic and another one of uncertain significance.
Conclusion
Thus, the frequency of mutations in patients with FH does not depend on the presence or absence of ACS. Both groups of patients are patients of a very high risk of developing both primary and repeated cardiovascular events.
ANALYSIS OF THE TRADITIONAL RISK FACTORS INFLUENCE ON DEVELOPMENT OF ISCHEMIC HEART DISEASE IN FAMILIAL HYPERCHOLESTEROLEMIA
