Familial Hypercholesterolemia Genetic Variations and Long-Term Cardiovascular Outcomes in Patients with Hypercholesterolemia Who Underwent Coronary Angiography.

Wen-Jane Lee,Tzu-Hung Hsiao,Wen-Lieng Lee,Jun-Peng Chen,Hsin Tung,I-Te Lee,Wayne Huey-Herng Sheu,Han-Ni Chuang,Ching-Heng Lin,Jun-Sing Wang,Yi-Ming Chen,Hsueh-Ju Lin,Kae-Woei Liang

doi:10.3390/genes12091413

Abstract

Background: Familial hypercholesterolemia (FH) has been associated with early coronary artery disease (CAD) and increased risk of atherosclerotic cardiovascular disease. However, the prevalence of FH and its long-term outcomes in a CAD-high-risk cohort, defined as patients with hypercholesteremia who underwent coronary angiography, remains unknown. Besides, studies regarding the impact of genetic variations in FH on long-term cardiovascular (CV) outcomes are scarce. Methods and Results: In total, 285 patients hospitalized for coronary angiography with blood low-density lipoprotein cholesterol (LDL-C) levels ≥ 160 mg/dL were sequenced to detect FH genetic variations in LDL receptors apolipoprotein B and proprotein convertase subtilisin/kexin type 9. Risk factors associated with long-term CV outcomes were evaluated. The prevalence of FH was high (14.4%). CAD and early CAD were significantly more prevalent among FH variation carriers than non-carriers, despite comparable blood LDL-C levels. Moreover, the FH variation carriers also underwent more revascularization after a mean follow-up of 6.1 years. Multivariate logistic regression demonstrated that FH genetic variation was associated with increased incidence of cardiovascular disease and mortality (odds ratio = 3.17, p = 0.047). Two common FH variants, LDLR c.986G>A and LDLR c.268G>A, showed the most significant impacts on high blood LDL-C levels and early-onset CAD. Conclusions: Our results indicate that FH genetic variants may exhibit differential effects on early-onset CAD and revascularization risks in patients undergoing coronary angiography. FH genetic information might help identify high-risk patients with typical CAD symptoms for appropriate intervention.

Highlights

Familial hypercholesterolemia (FH) is an autosomal dominant disease mainly caused by pathogenic variants of the genes involved in cholesterol metabolism, resulting in impaired clearance of circulating low-density lipoprotein cholesterol (LDL-C)
Forty-one of the 285 study patients were identified as FH based on detected pathogenic/likely pathogenic variants on their LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin kexin 9 (PCSK9) gene, which equated to a prevalence as high as 14.4%
We found that the prevalence rates of coronary artery disease (CAD) and early-onset CAD were significantly higher among the FH variant carriers (87.8% vs. 71.7%, p = 0.048 and 26.8% vs. 9.8%, p = 0.005, respectively)

Summary

Introduction

Familial hypercholesterolemia (FH) is an autosomal dominant disease mainly caused by pathogenic variants of the genes involved in cholesterol metabolism, resulting in impaired clearance of circulating low-density lipoprotein cholesterol (LDL-C). Substantial studies have examined the high prevalence of FH in patients with coronary artery disease (CAD; 9.7–9.4%) compared with the general population [9,10], based on the clinical criteria. Familial hypercholesterolemia (FH) has been associated with early coronary artery disease (CAD) and increased risk of atherosclerotic cardiovascular disease. The prevalence of FH and its long-term outcomes in a CAD-high-risk cohort, defined as patients with hypercholesteremia who underwent coronary angiography, remains unknown. Two common FH variants, LDLR c.986G>A and LDLR c.268G>A, showed the most significant impacts on high blood LDL-C levels and early-onset CAD. Conclusions: Our results indicate that FH genetic variants may exhibit differential effects on early-onset CAD and revascularization risks in patients undergoing coronary angiography

Methods

Results

Conclusion