Multisystem comorbidities and shared genetic pathways in calcific aortic stenosis: a phenome-wide and Mendelian...

Area of Science:

• Cardiovascular Medicine
• Genetics
• Epidemiology

Background:

• Calcific aortic stenosis (CAS) often co-occurs with systemic diseases, but their links and genetic basis are unclear.
• Understanding these relationships is crucial for managing CAS patients comprehensively.

Purpose of the Study:

• To map the network of CAS comorbidities across multiple body systems.
• To identify shared genetic mechanisms underlying CAS and its associated conditions.

Main Methods:

• Utilized UK Biobank data (467,484 participants) for observational and polygenic phenome-wide association studies.
• Employed disease-trajectory analyses and two-sample Mendelian randomization (MR) with FinnGen data.
• Assessed the role of LPA variants and plasma lipoprotein(a) (Lp(a)) using polygenic risk score (PRS) analyses.

Main Results:

• CAS showed associations with 42 cardiovascular and non-cardiovascular conditions, notably metabolic, endocrine, hematologic, and respiratory disorders.
• Circulatory and metabolic diseases often preceded other comorbidities in CAS trajectories.
• MR supported causal links from CAS to cardiovascular diseases, iron-deficiency anemia, mental disorders, and pleural effusion, largely mediated by LPA/Lp(a).

Conclusions:

• CAS is part of a wide multisystem comorbidity network, significantly influenced by genetic variation at LPA and elevated Lp(a).
• These findings reveal pleiotropic effects linking valvular calcification to systemic diseases.
• Targeting LPA presents a potential therapeutic strategy to alleviate the systemic burden of CAS.