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. 2021 Apr 13:8:625852.
doi: 10.3389/fcvm.2021.625852. eCollection 2021.

Prevalence and Impact of Apolipoprotein E7 on LDL Cholesterol Among Patients With Familial Hypercholesterolemia

Hayato Tada  1 , Kan Yamagami  1 , Nobuko Kojima  1 , Junichi Shibayama  1 , Tetsuo Nishikawa  1 , Hirofumi Okada  1 , Akihiro Nomura  1 , Soichiro Usui  1 , Kenji Sakata  1 , Masayuki Takamura  1 , Masa-Aki Kawashiri  1
Affiliations

Prevalence and Impact of Apolipoprotein E7 on LDL Cholesterol Among Patients With Familial Hypercholesterolemia

Hayato Tada et al. Front Cardiovasc Med. .

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.

Keywords: APOE; LDL-C; LDLR; PCSK9; familial hypercholesterolemia.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Analytic scheme in this study. Patients with FH were classified into four groups based on the status of FH mutation and APOE7 mutant (Groups 1–4). White indicates patients without mutations. Pink indicates patients with APOE7 mutant. Light blue indicates patients with a mutation in FH genes. Purple indicates patients with a mutation in FH genes and APOE7 mutant.
Figure 2
Figure 2
Impact of FH gene and APOE7 on LDL cholesterol. Boxplots are showing LDL cholesterol. *p < 0.05 and **p < 0.001. Analyses of variance followed by Tukey post-hoc test were used to test the differences among the groups.
Figure 3
Figure 3
Impact of FH gene and APOE7 on (A) triglyceride and (B) RLP cholesterol levels. Boxplots are showing triglyceride and RLP cholesterol. #x0002A;p < 0.05. Analyses of variance followed by Tukey post-hoc test were used to test the differences among the groups.
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