Monogenic familial hypercholesterolaemia confers excess premature cardiovascular risk beyond LDL-C: a family-lineage and LDL-C–matched analysis

Background Familial hypercholesterolaemia (FH) is an inherited disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular risk. In adults, FH-causing mutations are associated with higher cardiovascular risk even after accounting for LDL-C concentration. Objective To assess whether monogenic FH is associated with a higher burden of premature cardiovascular events in families independent of LDL-C levels. Methods In a paediatric FH screening cohort, we identified the affected parental lineage (maternal or paternal) in families of children with monogenic FH using genetic and/or clinical parameters. Cardiovascular risk was assessed by comparing the prevalence of premature cardiovascular events in parents and grandparents on the affected versus unaffected family side. Separately, children with monogenic FH were matched 1:2 by LDL-C with children without a pathogenic variant to compare family-history-based cardiovascular risk at similar LDL-C levels. Results The affected adult family member could be identified in 183 families (86 maternal, 97 paternal). The affected family side had a sixfold higher prevalence of premature cardiovascular events in parents and/or grandparents than the unaffected side, mainly driven by premature myocardial infarction (31.2% vs. 4.9%; p < 0.001), while premature stroke did not differ (2.2% vs. 2.7%; p = 0.74) (Figure 1). In the LDL-C–matched analysis, 119 children with monogenic FH were matched with 238 genetically negative children (LDL-C 156 mg/dL vs. 157 mg/dL). Families of children with monogenic FH had a higher prevalence of premature cardiovascular disease in parents and grandparents than LDL-C–matched genetically negative controls (47.9% vs. 35.7%; 1.4-fold difference) (Figure 2). Conclusion Families carrying monogenic FH show a substantially higher burden of premature cardiovascular events that is not explained by LDL-C levels alone. These findings support incorporating genetic testing and cascade screening into clinical practice to identify at-risk individuals early and prevent premature cardiovascular disease.Figure 1Figure 2