Abstract
Background: It has been suggested that a rare mutant apolipoprotein E7, APOE7 (p.Glu262Lys, p.Glu263Lys), has been identified to be associated with hyperlipoproteinemia in the general population. Moreover, its prevalence has been shown to be 0.005–0.06%. However, there are no prior data regarding its prevalence and impact on serum lipids in patients with familial hypercholesterolemia (FH).Methods: We recruited 1,138 patients with clinically diagnosed FH [mean age = 48, men = 512, median low-density lipoprotein (LDL) cholesterol = 231 mg/dl]. The coding regions of three FH genes (LDLR, APOB, and PCSK9) and apolipoprotein E (APOE) gene were sequenced. We investigated the prevalence and impact of APOE7 mutant on serum lipid levels in patients with FH.Results: We identified 29 patients (2.5 %) with a mutant APOE7 (heterozygote), which is apparently much higher than that of the general population. Moreover, when we focus on those without FH mutation (n = 540), we identified 21 patients (3.9 %) with a mutant APOE7. Patients with a mutant APOE7 exhibited significantly higher median LDL cholesterol and triglyceride levels compared with those without this rare mutant (249 vs. 218 mg/dl, p < 0.05, 216 vs. 164 mg/dl, p < 0.05, respectively). Moreover, LDL cholesterol levels in the APOE7-oligogenic FH individuals, with a pathogenic mutation in FH genes and APOE7 mutant, were significantly higher than that in monogenic FH patients (265 vs. 245 mg/dl, p < 0.05).Conclusion: We identified more patients with a mutant APOE7 than expected among those diagnosed with FH clinically, especially among those without FH-causing mutation. This implies a mutant APOE7 may be one of the causes FH, especially among those without FH mutations.
Highlights
Patients with familial hypercholesterolemia (FH), caused by genetic mutations in low-density lipoprotein (LDL)-associated genes (FH genes), are typically exhibiting extreme hyper-LDL cholesterolemia, tendinous xanthomas, and premature atherosclerotic cardiovascular disease (ASCVD) [1, 2]
It has been shown that additional lysine residues of apoE7 were associated with reduced binding affinity to LDL receptor (LDLR) and increased affinity to heparin; both of those features appear to lead to their atherogenic lipoprotein profile [8]
Multivariate linear analyses revealed that one mutation in the FH genes increased LDL cholesterol level by 46 mg/dl, while an APOE7 mutant elevated LDL cholesterol by 31 mg/dl
Summary
Patients with familial hypercholesterolemia (FH), caused by genetic mutations in low-density lipoprotein (LDL)-associated genes (FH genes), are typically exhibiting extreme hyper-LDL cholesterolemia, tendinous xanthomas, and premature atherosclerotic cardiovascular disease (ASCVD) [1, 2]. Even though it is a genetic disorder, at least a part of clinically diagnosed FH. The APOE is highly polymorphic: APOEε2 (cys112/cys158), APOE-ε3 (cys112/arg158), and APOE-ε4 (arg112/arg158) [5, 6] These common polymorphisms have been associated with LDL cholesterol levels [7]. There are no prior data regarding its prevalence and impact on serum lipids in patients with familial hypercholesterolemia (FH)
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