Systemic Sclerosis and Clinically Consequential Aortic Stenosis: Real-World and Human Genetic Evidence

This study will investigate the relationship between systemic sclerosis (SSc) and clinically consequential aortic stenosis using complementary real-world and human genetic approaches. The real-world component will use longitudinal data from the TriNetX research network to evaluate whether patients with SSc have an increased subsequent risk of aortic valve replacement, including transcatheter and surgical aortic valve replacement (TAVR/SAVR), compared with individuals without SSc. Incident aortic stenosis and related clinically relevant outcomes will be examined as secondary analyses. The genetic component will investigate whether genetic liability to SSc is associated with aortic stenosis using genome-wide association study summary statistics and Mendelian randomization. Shared genetic architecture between SSc and aortic stenosis will additionally be explored using local genetic correlation analyses, including LAVA where methodologically appropriate. The clinical and genetic analyses will be conducted as complementary and initially independent evidence streams. Their findings will subsequently be interpreted together to assess the consistency of epidemiological and human genetic evidence linking SSc with clinically significant aortic valve disease.