Impact of Monogenic Familial Hypercholesterolemia on Cardiovascular Risk in Affected Families: Data from the VRONI Study

J. Krefting (München)¹, R. S. Schmieder (München)¹, F. Sammer (München)², L. D. Schlieben (München)³, S. Arens (Hannover)⁴, O. Kordonouri (Hannover)⁵, M. Sander (München)⁶, S. Holdenrieder (München)⁷, T. Meitinger (Neuherberg)⁸, W. Koenig (München)¹, G. Leipold (Regensburg)⁹, H. Prokisch¹⁰, M. von Scheidt (München)¹, H. Schunkert (München)¹, V. Sanin (München)^2
1Deutsches Herzzentrum München Klinik für Herz- und Kreislauferkrankungen München, Deutschland; ²Deutsches Herzzentrum München Erwachsenenkardiologie München, Deutschland; ³Technical University of Munich Institute of Human Genetics - School of Medicine München, Deutschland; ⁴Kinderkrankenhaus auf der Bult Allgemeine Kinderheilkunde, Diabetologie, Endokrinologie, Klinische Forschung, Kindergastr Hannover, Deutschland; ⁵Ärztliche Direktorin Kinder- und Jugendkrankenhaus AUF DER BULT Hannover, Deutschland; ⁶Deutsches Herzzentrum München, TUM Universitätsklinikum München, Deutschland; ⁷Deutsches Herzzentrum München Institut für Laboratoriumsmedizin München, Deutschland; ⁸Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Institute of Human Genetics Neuherberg, Deutschland; ⁹Regensburg, Deutschland; ¹⁰Deutschland

Introduction:
Familial hypercholesterolaemia (FH) is an inherited disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels and an increased risk of cardiovascular disease. In adults, the presence of FH-causing mutations has been associated with a significantly higher cardiovascular risk, even after accounting for LDL-C concentrations.

Methods:
Within the paediatric VRONI cohort, we identified the affected parental lineage (maternal or paternal) of children with monogenic FH based on genetic or clinical parameters. Cardiovascular risk was assessed in affected versus unaffected family members using the prevalence of premature cardiovascular events in the parents and grandparents of the index child as a surrogate marker. In a separate analysis, children with monogenic FH were matched in a 1:2 ratio by LDL-C levels with children without a pathogenic mutation to compare family history–based cardiovascular risk independently of LDL-C concentration.

Results:
The affected adult family member could be identified in 183 families (86 maternal, 97 paternal). The affected side showed a sixfold higher incidence of premature cardiovascular events in parents and/or grandparents compared with the unaffected side, mainly due to higher rates of premature myocardial infarction (31.2% vs. 4.9%; p < 0.001), while the incidence of premature stroke did not differ significantly (2.2% vs. 2.7%; p = 0.74). In the LDL-C–matched analysis, 119 children with monogenic FH were paired with 238 without FH (LDL-C: 156 mg/dL vs. 157 mg/dL). Families of children with FH had a 1.4-fold higher prevalence of premature cardiovascular disease in the parental and grandparental generations than genetically negative controls with the same LDL-C levels (47.9% vs. 35.7%).

Conclusion:
The family side carrying monogenic FH showed a significantly higher burden of premature cardiovascular events, independent of LDL-C levels. These findings highlight the contribution of genetic predisposition beyond lipid levels and underscore the importance of incorporating genetic testing and cascade screening into clinical practice to identify at-risk individuals early and prevent premature cardiovascular disease.