Paternal inheritance predicts earlier cardiovascular event onset in patients with familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disease, with an autosomal codominant inheritance, predisposing to premature atherosclerotic cardiovascular disease (ASCVD). Paternal or maternal inheritance of the FH-causing mutation may affect the FH phenotype in offspring, but the effect of the genetic transmission on cardiovascular disease risk remains to be established. The aim of the present study is to compare the incidence of cardiovascular events between patients with maternal vs paternal inheritance of familial hypercholesterolemia.

We prospectively studied 725 genetically-confirmed FH patients (33,805 person-years), including 268 with maternal inheritance and 321 with paternal inheritance of the mutation. ASCVD was defined as angina, myocardial infarction, coronary angioplasty, coronary bypass surgery, claudication, peripheral angioplasty, peripheral arterial surgery, transient ischemic attack, stroke, carotid endarterectomy and CV death. Cox-proportional hazard models and Kaplan-Meier analysis were used to compare the two groups.

Before 50 years of age, paternal inheritance of FH was associated with a 1.5-fold increased risk for ASCVD, as compared to maternal inheritance (HR 1.59, 95% CI 1.11-2.28, p = 0.01). This association remained significant after adjusting for confounding factors (HR 1.49, 95% CI 1.00-2.23, p = 0.05). The age of first ASCVD event was also significantly lower in the paternal inheritance group (42 years) than in the maternal inheritance group (46 years), p = 0.02.

This study suggests that paternal inheritance of the FH-causing mutation was associated with an earlier cardiovascular event onset compared to maternal inheritance. The mechanisms behind these findings remain to be established.