Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease

Area of Science:

• Cardiovascular Genetics
• Genomics
• Epidemiology

Background:

• Aortic stenosis (AS) and coronary artery disease (CAD) often coexist, but their distinct genetic and cardiovascular risk factors remain unclear.
• Understanding shared versus specific risk factors is crucial for targeted prevention and treatment.

Purpose of the Study:

• To identify genetic risk loci and cardiovascular risk factors specifically associated with AS, differentiating them from CAD.
• To elucidate the genetic architecture underlying AS.

Main Methods:

• A genomewide association study (GWAS) of AS was conducted, adjusting for comorbid CAD.
• Utilized large biobank cohorts (EGAS, UK Biobank, Estonian Biobank, FinnGen) with European ancestry.
• Performed follow-up analyses including cardiovascular traits, tissue transcriptome data, and Mendelian randomization.

Main Results:

• Identified 17 AS risk loci, with 11 showing AS-specific associations not linked to CAD.
• Serum phosphate emerged as an AS-specific risk factor, unlike in CAD.
• Blood pressure, BMI, and cholesterol metabolism showed weaker associations with AS compared to CAD.

Conclusions:

• A distinct genetic risk profile exists for AS at both single-marker and polygenic levels.
• These findings offer novel genetic targets for future AS research and therapeutic development.
• Differentiating AS and CAD genetic underpinnings can refine clinical risk stratification.