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Familial hypercholesterolemia and familial defective apolipoprotein B-100: comparison of the phenotypic expression In
D Brugger1, H Schuster, N Zöllner
1Medizinische Poliklinik, University of Munich, Pettenkoferstr. 8a, Munich D-80336, Germany.
Insights
Familial hypercholesterolemia (FH) patients with low-density lipoprotein receptor (LDLR) gene defects show significantly higher risks of coronary artery disease (CAD) compared to those with familial defective apolipoprotein B-100 (FDB). LDLR defects lead to more severe hypercholesterolemia and atherosclerosis.
Area of Science:
- Cardiovascular Genetics
- Metabolic Disorders
- Atherosclerosis Research
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL cholesterol, tendon xanthomas, and premature coronary artery disease (CAD).
- FH results from mutations in the low-density lipoprotein receptor (LDLR) gene or the apolipoprotein B gene (familial defective apolipoprotein B-100, FDB).
- Understanding the differential phenotypic expression of these genetic defects is crucial for risk stratification and management.
Purpose of the Study:
- To compare the clinical and phenotypic manifestations of LDLR gene defects versus FDB mutations in FH patients.
- To assess the prevalence of CAD and atherosclerotic plaques in patients with either LDLR defects or FDB.
- To investigate the relationship between genetic defects and cardiovascular risk factors in a German cohort.
Main Methods:
- Prospective ascertainment of 83 patients with LDLR defects (76 heterozygous, 7 homozygous) and 33 heterozygous FDB patients from a lipid clinic in Germany.
- Genetic testing for the G-A mutation in exon 26 of the apolipoprotein B gene for FDB diagnosis.
- Analysis of plasma lipid levels, CAD prevalence, myocardial infarction, coronary artery bypass graft, coronary angiography results, and carotid artery plaques, considering other CAD risk factors.
Main Results:
- LDLR defect patients exhibited significantly higher average total cholesterol (413.7 mg/dl) compared to FDB patients (321.8 mg/dl).
- Patients with LDLR defects had a substantially higher risk of CAD (33% prevalence), myocardial infarction, and coronary revascularization compared to FDB patients (no severe CAD).
- Atherosclerotic plaques in the carotid arteries were more prevalent in LDLR defect patients (82%) than in FDB patients (52%).
Conclusions:
- LDLR gene defects are associated with more severe hypercholesterolemia and a significantly higher incidence of premature atherosclerosis and CAD than FDB mutations.
- The observed differences in CAD risk may extend beyond elevated LDL levels, potentially involving broader lipoprotein metabolism disruptions in LDLR defects.
- These findings highlight the importance of distinguishing between genetic causes of FH for accurate prognostication and tailored therapeutic strategies.
Abstract:
Familial hypercholesterolemia (FH) is characterized by an increased level of LDL cholesterol, tendon xanthomas and an elevated risk of premature coronary artery disease (CAD). FH is caused by different mutations in the low density lipoprotein receptor (LDLR) gene or by a G to A mutation in exon 26 of the apolipoprotein B gene causing familial defective apolipoprotein B-100 (FDB). To compare the phenotypic expression of either defect, we studied 83 patients (76 heterozygous and 7 homozygous persons) with LDLR defects and 33 heterozygous FDB patients from Germany. We took into account other risk factors for CAD. In contrast to earlier studies, our patients where prospectively ascertained from the lipid clinic and tested for the G-A mutation. The average total cholesterol level in plasma was 413.7 mg/dl in LDLR patients and 321.8 mg/dl in FDB patients. Patients with LDLR defects had a significantly higher risk of myocardial infarction, coronary artery bypass graft, positive coronary angiography, atherosclerotic plaques in the carotid arteries and CAD (p<0.01) than patients with FDB. CAD was present in 33% and plaques in the carotid arteries in 82% of the patients with LDLR defects. No patient with FDB had severe CAD, while only 52% had plaques in the carotid arteries (p<0.05). Thus in our study, hypercholesterolemia and premature atherosclerosis were more common in LDLR patients than in FDB patients. We believe that the striking difference in CHD incidence is not sufficiently explained by the higher LDL levels in LDLR patients. A possible explanation may be that in LDLR patients, the metabolism of low density lipoproteins, intermediate density lipoproteins and very low density lipoproteins is disrupted, whereas in FDB patients there is only disruption in apo B-containing LDL.