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

Abstract

Background: Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke.

Methods and results: Cross-ancestry meta-analysis of genome-wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single-nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2-sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome-wide association studies consortia. Our cross-ancestry meta-analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP. Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03-1.11) for CAD, 1.10 (95% CI, 1.01-1.20) for CHF, and 1.13 (95% CI, 1.09-1.18) for stroke. The results were consistent among the European population.

Conclusions: Our 2-sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.

Keywords: Mendelian randomization; cardiovascular disease; cross‐ancestry meta‐analysis; genome‐wide association studies; primary aldosteronism.

Figure 1. Manhattan plot for the cross‐ancestry meta‐analysis of genome‐wide association studies of primary aldosteronism.

This is an updated cross‐ancestry meta‐analysis combining the most recent Japanese, UK Biobank, FinnGen, and French GWAS (1560 PA cases and 726 761 controls). The horizontal axis represents the genome in physical order and the vertical axis shows −log₁₀(P value) for association of individual variants with PA in the cross‐ancestry meta‐analysis. The red horizontal line indicates the genome‐wide significance threshold (P=5.0×10⁻⁸). The lead variants of genome‐wide association loci were marked with their nearest genes. GWAS indicates genome‐wide association studies; and PA, primary aldosteronism.

Figure 2. Plot of Mendelian randomization analyses regarding the association between primary aldosteronism and risk of coronary artery diseases, congestive heart failure, and stroke.

A, The association between PA and coronary artery disease among East Asian population. B, The association between PA and congestive heart failure among East Asian population. C, The association between PA and stroke among East Asian population. D, The association between PA and coronary artery disease among European population. E, The association between PA and congestive heart failure among European population. F, The association between PA and stroke among European population. MR indicates Mendelian randomization; PA, primary aldosteronism; and SNV, single nucleotide variant.