| Title: | Synergic combination of the monogenic ANGPTL3 p.H343R variant and a polygenic predisposition in a family with hypobetalipoproteinemia |
| Journal: | Atherosclerosis |
| Published: | 4 Nov 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41206978/ |
| DOI: | https://doi.org/10.1016/j.atherosclerosis.2025.120569 |
Publication 19060
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Abstract
BACKGROUND AND AIMS: Primary hypobetalipoproteinemia (HBL) is mostly due to a polygenic origin or to monogenic disorders including loss of function (LOF) variants in APOB, much less frequently Angiopoietin-like 3 gene (ANGPTL3). A new heterozygous variant of uncertain significance (VUS), p.H343R missense variant in ANGPTL3 cosegregated with HBL in a family. The aim of the present study was to assess in vitro the functionality of this variant and to establish its causality in this family.</p>
METHODS: Targeted next-generation sequencing was performed in the proband to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score (PRSLDL-C). The effect of the variant was investigated by assessing the ANGPTL3 protein secretion in vitro. A replication study was performed in the UK-biobank.</p>
RESULTS: All 8 HBL subjects had PRSLDL-C below the first decile, supporting a polygenic HBL. Six family members also carrying the p.H343R variant (n = 6) had a significantly lower LDL-C than the polygenic members non-carriers of the p.H343R (n = 2) (p=0.012). In vitro, p.H343R variant significantly decreased ANGPTL3 concentration in the medium (-82 %, p=0.029) and the ratio of secretion (0.28 ± 0.06 vs. 1.00 ± 0.30 p=0.029, n = 3) compared to the wild-type. The synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition was confirmed in the UK biobank.</p>
CONCLUSIONS: This study shows that the novel ANGPTL3-p.H343R variant decreases ANGPTL3 secretion in vitro and can now be considered as a LOF variant. The lipid phenotype in this family results from a synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition.</p>
16 Keywords
- Adult
- Angiopoietin-Like Protein 3
- Angiopoietin-like Proteins
- Cholesterol, LDL
- Female
- Genetic Predisposition to Disease
- Heredity
- Heterozygote
- Humans
- Hypobetalipoproteinemias
- Male
- Middle Aged
- Multifactorial Inheritance
- Mutation, Missense
- Pedigree
- Phenotype
11 Authors
- Manon Levy
- Alexandre Janin
- Oriane Marmontel
- Anthony Fourier
- Séverine Nony
- Antoine Rimbert
- Bertrand Cariou
- Sylvie Villar-Fimbel
- Sybil Charrière
- Philippe Moulin
- Mathilde Di Filippo
1 Application
| Application ID | Title |
|---|---|
| 49823 | Genetic predisposition to cardiovascular and metabolic diseases |
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