Lipids & metabolic liver disease
A Low-Frequency APOB p.(Pro955Ser) Variant Contributes to the Severity of/Variability in Familial Hypercholesterolemia
An erratum to this article was published (J Clin Endocrinol Metab, 14 Jul 2023 ↗)
Main finding · Allele frequency of APOB c.2863C > T:p.(Pro955Ser)Result — go to the resultOdds ratio 4.9 95% CI 3.4–7.1Authors' conclusion
The low-frequency APOB c.2863C > T:p.(Pro955Ser) variant is not an FH-causative variant, but it has a moderate effect size in HeFH. These findings suggest that the combination of the APOB c.2863C > T:p.(Pro955Ser) variant and age, environmental factors, or other genetic factors contributes to the severity of or variability in the HeFH phenotype.
Study context
- Population
- Families with heterozygous familial hypercholesterolemia (HeFH) without pathogenic variants in the LDLR or PCSK9 genes122 families
- Participants
- 215 participants
- Comparison
- APOB p. allele frequency in HeFH probands vs general Japanese population
- Outcome
- Allele frequency of APOB c.2863C > T:p.(Pro955Ser)
Methodological detailswhole-exome sequencing, family-based
- Whole-exome sequencing
- Family-based
Main finding
As reported in the abstract
Odds ratio
4.9
95% CI 3.4–7.1
P = 6.9 × 10-13
By group
HeFH probands
0.15
General Japanese population
0.034
- Nonsynonymous APOB variants identified
- 24
Further findings
Carriers of p.(Pro955Ser) among unrelated HeFH patients (n = 645)
- Carriers
- 9.8% (n = 63)
- Penetrance in pedigree-based analysis
- low
In vitro low-density lipoprotein (LDL) uptake
- LDL uptake with homozygous p.(Pro955Ser) vs control subjects
- 44%
- Similar to LDL uptake with known pathogenic heterozygous p.(Arg3527Gln)
Original publication
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