LDLR activity and cardiovascular burden in Portuguese families with Familial Hypercholesterolemia

Miranda, Beatriz Raposo; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, Mafalda

http://hdl.handle.net/10400.18/8924

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Authors

Miranda, Beatriz Raposo

Medeiros, Ana Margarida

Alves, Ana Catarina

Bourbon, Mafalda

Abstract(s)

Familial hypercholesterolemia (FH) is the most common inherited disorder of lipid metabolism and is clinically characterized by elevated plasma cholesterol, which predisposes to cardiovascular disease (CVD). In nearly 90% of the cases, FH is caused by a pathogenic/likely pathogenic variant in the LDLR gene. In this work, we aimed to compare the cardiovascular burden in families from the Portuguese FH Study (PFHS) carrying different LDLR variants functionally studied. The PFHS database (containing clinical and molecular characterization of individuals referred to the PFHS) was consulted. Considering well-documented personal and familial history of CVD, a total of 246 PFHS families carrying LDLR causative variants (previously functionally characterized) were selected for this study. According to the results of functional assays reported, 47 different pathogenic/likely pathogenic variants (found in 617 subjects) were divided into 3 cut-offs of LDLR activity: < 5% (n=15), 5-30% (n=16), and 30-70% (n=16). Within 80 families carrying variants with a LDLR activity of <5% (214 participants), 10% of individuals suffered at least one cardiovascular event (mainly myocardial infarction) at medium age of 44 years, and the majority reported familial history of CVD in more than 2 generations. In 115 families carrying variants with LDLR activity between 5-30% (280 participants), 7% of the subjects had a cardiovascular event at medium age of 41. It is relevant to note that the individuals presenting CVD had, specifically, variants showing less than 15% of activity. Despite comparatively fewer subjects (only 123), in 51 families carrying variants with a LDLR activity of 30-70%, we observed that 12% of them reported development of CVD at notably older age (medium of 51). Since several LDLR variants greatly impair LDLR function and activity, some are highly associated with premature CDV. Considering the cardiovascular burden of individuals with FH, the early identification of these individuals alongside functional characterization of variants discovered within the PFHS can contribute to an improved and personalized disease management.