The Genomic Landscape of Aortic Valve Stenosis and Mitral Valve Prolapse: Insights into Disease Susceptibility

Valvular heart diseases (VHD) represent an important global health burden, yet no pharmacological therapy exists to prevent or slow their progression. This comprehensive review describes advances in genetic discoveries for aortic valve stenosis (AS) and mitral valve prolapse (MVP) over the past decades. Familial studies allowed the identification of a few rare monogenic forms of AS, most of which are associated with congenital bicuspid aortic valve. Large-scale genome-wide association studies (GWAS) have mapped 268 independent risk loci for AS. The genetic variants identified implicate lipid metabolism, inflammation, blood pressure regulation, and calcification as important determinants. MVP is a feature of genetic syndromes, many of them involving the TGF-β signaling pathway. Nonsyndromic monogenic causes have also been identified. Common variants at 20 loci have been associated with MVP by GWAS. Some of these variants are also linked to cardiomyopathy, left ventricular dimensions, and arrhythmias, suggesting a relationship with myocardial pathology. Mendelian randomization has moved beyond genetic associations to establish lipoprotein (a) (Lp(a)), LDL-cholesterol (LDL-C), triglycerides, systolic blood pressure (SBP), and body mass index (BMI) as causal risk factors for AS while revealing protective effects of body size-related measures in MVP. Emerging polygenic risk scores (PRS) achieved significant risk prediction for both diseases, representing promising tools for early identification of high-risk individuals before clinical manifestation. Summarizing genetic evidence from GWAS, causal inference, and risk prediction, this review provides a roadmap for future research and clinical translation, emphasizing the urgent need for prospective trials testing genetically-informed interventions for VHD prevention.