Abstract
BACKGROUND: Familial hypercholesterolemia (FH) is a genetic condition characterized by elevated LDL-C and increased cardiovascular risk. Beyond LDL-C levels, the impact of genotype on glucose homeostasis has not been well evaluated. We aimed to evaluate the impact of genotype on glycemic status and on atherosclerotic injury in FH subjects. METHODS: We conducted a cross-sectional study on 322 FH subjects not on lipid-lowering therapy and without history of cardiovascular disease. Biochemical and genetic analyses as well as vascular profile assessment were obtained from all subjects. The study population was divided into two groups according to genotype: LDL receptor (LDLR) group and non-LDLR (NLDLR) group. RESULTS: The LDLR group exhibited a higher prevalence of low glycemic status (LGS) than the NLDLR group (44.1% vs. 26%, p < 0.01), whereas a high glycemic status (HGS) was more prevalent in the NLDLR group compared with LDLR group (74% vs. 55.9%, p < 0.01). The NLDLR group exhibited a higher prevalence of peripheral atherosclerotic plaques than the LDLR group (93.4% vs. 73%, p < 0.05), while coronary artery calcification (CAC) presence was more prevalent in the LDLR group compared with the NLDLR group (74.7% vs. 48%, p < 0.01). In a secondary analysis the study population was stratified into three groups based on LDLR genotype: NLDLR, LDLR defective, LDLR null groups. The prevalence of LGS progressively increased from the NLDLR to the LDLR null group, while HGS showed an inverse trend (p for trend < 0.05). Peripheral atherosclerotic plaque prevalence decreased from the NLDLR to the LDLR null group (p for trend < 0.05), while CAC prevalence increased progressively in the three groups (p for trend < 0.01). Logistic regression analysis showed that FH groups with an LDLR mutation were inversely associated with HGS (p for both < 0.01) and the LDLR null group exhibited the strongest association. CONCLUSIONS: FH subjects with NLDLR mutations exhibited a worse glycemic profile, while null LDLR mutations showed the strongest inverse association with HGS. The integrations of genetic, lipid and glucose data could be useful to better identify the metabolic profile and the atherosclerosis distribution in FH subjects. RESEARCH INSIGHTS: WHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: Familial hypercholesterolemia (FH) is characterized by elevated LDL-C levels. LDLR null mutations protected pancreatic β-cells from cholesterol accumulation. NGS has improved FH diagnosis by analysis of all genes implicated in the lipid disorder. WHAT IS THE KEY RESEARCH QUESTION?: What is the impact of FH genotype (monogenic with or without LDLR mutation/polygenic) on glycemic status? WHAT IS NEW?: FH population was characterized by a heterogeneous glycemic profile according to LDLR mutation. LDL-C and plasma glucose could modulate the distribution of subclinical atherosclerosis. HOW MIGHT THIS STUDYINFLUENCE CLINICAL PRACTICE?: Genetic, lipid, glucose data could better identify the metabolic and atherosclerotic profiles in FH.