Gene Mutation in Patients with Familial Hypercholesterolemia and Response to Alirocumab Treatment-A Single-Centre Analysis

Abstract

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by significantly elevated levels of low-density lipoprotein (LDL) cholesterol, which plays a major role in the progression of atherosclerosis and leads to a heightened risk of premature atherosclerotic cardiovascular disease. Methods: We have carried out an observational study on a group of 17 patients treated at the Outpatient Lipid Clinic from 2019 to 2024. Result: The most frequent mutation observed was found in the LDL receptor (LDLR) gene, which was identified in ten patients (58.8%). Five patients were identified to have a mutation in the apolipoprotein B (APOB) gene, whereas two patients had two points mutations, one in the LDLR, and the other in the APOB gene. The average age of patients with LDLR mutation was 54.8 (12.3); for APOB mutation it was 61.4 (9.3) and for patients with two points mutation it was 61.5 (14.8). The study results showed that at Week 12, individuals with LDLR-defective heterozygotes who were given alirocumab 150 mg every two weeks experienced a 63.0% reduction in LDL cholesterol levels. On the other hand, individuals with APOB heterozygotes experienced a 59% reduction in LDL cholesterol levels. However, in patients with double heterozygous for mutations in LDLR and APOB genes, there was a hyporesponsiveness to alirocumab, and the reduction in LDL-C was only by 23% in two individuals. Conclusions: In patients with a single mutation, there was a greater response to treatment with alirocumab in contrast to patients with double heterozygous mutation, who did not respond to treatment with PCSK9 inhibitors.

Keywords: APOB; LDLR; PCSK9; alirocumab; familial hypercholesterolemia; genes; hyperlipidemia.

Figure 1

The stages of participant inclusion in the study.

Figure 2

Mean percentage reduction from baseline in LDL-C level depending on the mutation after 12 weeks of treatment alirocumab in dose 150 mg sc. Abbreviations: APOB: apolipoprotein B gene; LDL-C: low-density lipoprotein cholesterol; LDLR: low-density lipoprotein receptor gene.

Figure 3

The LDL-C level fluctuations before and after a 12-week therapy of alirocumab for each patient. (A). Patients with LDLR mutation (n = 10). (B). Patients with APOB mutation (n = 5). (C). Patients with two genes mutation: APOB + LDLR (n = 2). Abbreviations APOB: Apolipoprotein B-100 gene; LDLR: Low-density lipoprotein receptor gene, LDL-C: lower-density lipoprotein concentration.