Gene-gene interactions protects against Familial Hypercholesterolemia: effect of lost of function PCSK9 variants
Rodriguez Novoa, S.; Martinez Hernandez, P.; Hidalgo Mayoral, I.; Herranz Cecilia, A.; Rodriguez Roca, N.; Carazo Alvarez, A.; Gallego Onis, N.; Duque Alcorta, M.; Rodriguez Jimenez, C.
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Background: Familial hypercholesterolemia (FH) is most frequently caused by pathogenic variants in LDLR, but phenotypic variability suggests the influence of genetic modifiers. Methods: We investigated a large multigenerational family with FH, combining clinical data, lipid profiles, and genetic analysis with functional studies. LDLR and PCSK9 variants were characterized according to ACMG/ClinGen guidelines. Functional assays in CHO-ldlA7 cells assessed LDLR activity, while plasma PCSK9 levels were quantified by ELISA. Results: LDLR c.2479G>A variant was associated with FH in the family. The presence of loss of function c.137G>T and c.2023del variants at PCSK9 appears to mitigate the effect of the LDLR variant. Conclusions: This study provides evidence that PCSK9 variants can counteract the deletereous effect of a LDLR variant associated with FH. These findings highlight the importance of gene/gene interactions in the clinical variability of FH and their potential implications for precision medicine.
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