Primary Aldosteronism and Risk of Cardiovascular Outcomes: Genome-Wide Association and Mendelian Randomization Study.

Area of Science:

• Cardiovascular Genetics
• Endocrinology
• Epidemiology

Background:

• Observational studies suggest a link between primary aldosteronism (PA) and adverse cardiovascular outcomes like coronary artery disease (CAD), congestive heart failure (CHF), and stroke.
• Establishing a causal relationship is hindered by a lack of randomized controlled trial data.
• This study investigates the causal role of PA in the development of CAD, CHF, and stroke.

Purpose of the Study:

• To determine the causal relationship between primary aldosteronism (PA) and the risk of incident coronary artery disease (CAD), congestive heart failure (CHF), and stroke.
• To leverage genetic variants associated with PA as instrumental variables in a Mendelian randomization analysis.
• To provide evidence supporting early screening and intervention for PA to mitigate cardiovascular risks.

Main Methods:

• A cross-ancestry meta-analysis of genome-wide association studies (GWAS) was performed to identify single-nucleotide variants (SNVs) associated with PA.
• Seven genetic loci significantly associated with PA risk were identified, including genes near CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP.
• A 2-sample Mendelian randomization analysis was conducted using these genetic variants as instrumental variables to assess the causal effect of PA on incident CAD, CHF, and stroke in East Asian and European populations.

Main Results:

• The cross-ancestry GWAS meta-analysis identified 7 genetic loci robustly associated with PA risk.
• Mendelian randomization analysis indicated that PA causally increases the risk of CAD (OR 1.07, 95% CI 1.03-1.11), CHF (OR 1.10, 95% CI 1.01-1.20), and stroke (OR 1.13, 95% CI 1.09-1.18) in the East Asian population.
• These causal associations were consistent across both East Asian and European ancestry populations.

Conclusions:

• Primary aldosteronism (PA) is causally associated with an increased risk of developing coronary artery disease (CAD), congestive heart failure (CHF), and stroke.
• These findings underscore the critical importance of early and proactive screening for PA.
• Timely identification and management of PA can potentially prevent future cardiovascular events.