Calcific aortic stenosis is linked to 42 higher risks of various conditions, primarily influenced by genetic variation in LPA and elevated plasma lipoprotein(a).
Does calcific aortic stenosis and its genetic susceptibility increase the risk of multisystem comorbidities?
Calcific aortic stenosis is associated with a broad multisystem comorbidity network, largely driven by pleiotropic genetic variation at the LPA locus and elevated Lp(a) levels.
Absolute Event Rate: 0% vs 0%
Background Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisystem comorbidity network of CAS and clarify underlying genetic mechanisms. Methods In 467 484 participants from the UK Biobank, observational and polygenic phenome-wide association studies evaluated associations between CAS and 1571 phenotypes, integrating disease-trajectory analyses to visualise temporal patterns. Associations replicated across observational and polygenic analyses were tested using two-sample Mendelian randomisation (MR) based on 22 CAS-related variants from FinnGen. Polygenic risk score (PRS) analyses excluding specific genes assessed their contributions, particularly LPA and plasma lipoprotein(a) (Lp(a)) levels. Results CAS was associated with higher risks of 42 cardiovascular and non-cardiovascular conditions, most prominently metabolic, endocrine, haematological and respiratory disorders. Temporal analyses showed that circulatory and metabolic diseases typically precede other comorbidities in CAS trajectories. MR findings were consistent with causal effects of CAS on multiple cardiovascular diseases, iron-deficiency anaemia, mental disorders and pleural effusion. When LPA variants were removed from the CAS PRS or plasma Lp(a) concentration was adjusted for, most associations lost significance, indicating a shared LPA/Lp(a)-mediated genetic pathway. Conclusions CAS is embedded within a broad multisystem comorbidity network, driven largely by genetic variation at LPA and elevated Lp(a). These findings highlight pleiotropic mechanisms linking valvular calcification with systemic disease and support LPA-targeted therapies as a promising avenue for reducing the multisystem burden of CAS.
Zhou et al. (Mon,) reported a other. Calcific aortic stenosis is linked to 42 higher risks of various conditions, primarily influenced by genetic variation in LPA and elevated plasma lipoprotein(a).