Additive Effect of APOE Rare Variants on the Phenotype of Familial Hypercholesterolemia
Abstract
Background: Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in LDLR , APOB , or PCSK9 genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in APOE . Here we study the phenotype of 21 adult patients, double heterozygotes for rare LDLR and rare APOE variants ( LDLR+APOE ) in a national wide French cohort. Methods: LDLR , APOB , PCSK9 , and APOE genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the LDLR+APOE carriers (n=21) and the carriers of the same LDLR causative variants alone (n=22). Results: The prevalence of LDLR+APOE carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in LDLR+APOE patients than in LDLR patients (9.14±2.51 versus 7.43±1.59 mmol/L, P=0 .0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in LDLR+APOE carriers than in LDLR carriers (10.83±3.45 versus 7.43±1.59 mmol/L, P=0 .0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in LDLR+APOE patients than in LDLR carriers (70% versus 30%, P=0 .026). Conclusions: Although an incomplete penetrance should be taken into account for APOE variant classification, these results suggest an additive effect of deleterious APOE variants on ADH phenotype highlighting the relevance of APOE sequencing.
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An additive effect of deleterious APOE variants on the FH phenotype was observed in the Marmontel 2023 study.
“An additive effect of deleterious APOE variants on the FH phenotype was observed.”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [40]
In the Marmontel 2023 study, lipid levels and the frequency of premature atherosclerotic cardiovascular diseases were compared between LDLR + APOE carriers (n = 21) and carriers of the same LDLR causative variants alone (n = 22).
“In the Marmontel 2023 study, the lipid levels and the frequency of premature atherosclerotic cardiovascular diseases were compared between the LDLR + APOE carriers (n = 21) and the carriers of the same LDLR causative variants alone (n = 22) [40].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [40]
Among patients with causal APOE variants in the Marmontel 2023 study, LDL-C levels were 46.0% higher in LDLR + APOE carriers than in LDLR carriers (mean 10.83 ± 3.45 versus 7.43 ± 1.59 mmol/L, p = 0.027), and premature atherosclerotic cardiovascular disease was more frequent (70.0% versus 30.0%, p = 0.026).
“Among patients with causal APOE variants, LDL-C levels were 46.0% higher in LDLR + APOE carriers than in LDLR carriers (mean 10.83 ± 3.45 versus 7.43 ± 1.59 mmol/L, p = 0.027), and premature atherosclerotic cardiovascular disease was more frequent (70.0% versus 30.0%, p = 0.026).”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [40]
p.Leu46Pro has been described in patients with FH and familial combined hyperlipidemia.
“Nevertheless, p.Leu46Pro has been described in patients with FH and familial combined hyperlipidemia [6,40].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [40]
In the Marmontel 2023 study, there were no differences in TG levels between LDLR + APOE carriers and LDLR carriers (mean 1.46 ± 0.58 versus 1.36 ± 0.62 mmol/L, p = 0589).
“Notably, there were no differences in TG levels (mean 1.46 ± 0.58 versus 1.36 ± 0.62 mmol/L, p = 0589) [40].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [40]
Cites
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594 · see citing works
Rall, S. C., Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.15.4696 · Cited by 345 · see citing works
Marduel, M., Ouguerram, K., Serre, V., Bonnefont-Rousselot, D., Marques-Pinheiro, A., Erik Berge, K., Devillers, M., Luc, G., Lecerf, J.-M., Tosolini, L., et al. (2013) · Human Mutation · doi:10.1002/humu.22215 · Cited by 133 · see citing works
Self-citationDijck-Brouwer, D. A. J., van Doormaal, J. J., Kema, I. P., Brugman, A. M., Kingma, A. W., & Muskiet, F. A. J. (2005) · Annals of Clinical Biochemistry: International Journal of Laboratory Medicine · doi:10.1258/0004563054255498 · Cited by 9 · see citing works
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Blokhina, A. V., Ershova, A. I., Kiseleva, A. V., Sotnikova, E. A., Zharikova, A. A., Zaicenoka, M., Vyatkin, Y. V., Ramensky, V. E., Kutsenko, V. A., Garbuzova, E. V., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312651 · Cited by 8 · see citing works
- Authors
- Marmontel, O., Abou-Khalil, Y., Bluteau, O., Cariou, B., Carreau, V., Charrière, S., Divry, E., Gallo, A., Moulin, P., Paillard, F., Peretti, N., Rabès, J.-P., Varret, M., Carrié, A., & Di Filippo, M.
- Affiliations
- Lyon 1 Université (FR)
- Université Paris Cité and Université Sorbonne Paris Nord, INSERM, LVTS, Paris, France (Y.A.-K., J.-P.R., M.V.).
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Service de Biochimie et Biologie moléculaire, Laboratoire de Biologie Médicale Multi-Sites (O.M., E.D., M.D.F.)
- Hôpital Pontchaillou (FR)
- Fédération d’Endocrinologie, Maladies Métaboliques, Diabète et Nutrition, GHE (S.C., P.M.)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2023-07
- Volume
- 43
- Issue
- 7
- Pages
- e270-e278
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W4367323352
- Cited by
- 9
- References
- 4
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 1
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Saint Joseph University
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- familial hypercholesterolemia, LDLR variants, autosomal dominant hypercholesterolemia, double heterozygosity, additive genetic effects, LDL cholesterol, premature atherosclerotic cardiovascular disease, homozygous familial hypercholesterolemia
- MeSH terms
- Proprotein Convertase 9, Apolipoproteins B, Apolipoproteins E, Heterozygote, Humans, Hyperlipoproteinemia Type II, Cholesterol, LDL, Mutation, Phenotype, Receptors, LDL, Atherosclerosis
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