Renin-independent aldosteronism and metabolic dysfunction-associated steatotic liver disease and cirrhosis: A genetic association study.

BACKGROUND & AIMS: Renin-independent aldosteronism (RIA) refers to a spectrum of autonomous aldosterone hypersecretion. We aimed to explore the genetical relationship between RIA and metabolic dysfunction-associated steatotic liver disease (MASLD) and cirrhosis.

METHODS

We included 125357 participants from the cohort of United Kingdom Biobank. We calculated a polygenic risk score (PRS) for RIA on the basis of reported data from genome-wide association studies, and performed an analysis of Phenome Wide Association Studies (PheWAS) on diverse outcomes. We explored the genetical relationship between RIA and MASLD or cirrhosis by using Mendelian randomization analysis.

RESULTS

An increased RIA PRS was associated with higher risks of MASLD and MASLD related cirrhosis, and the well-defined RIA related target organ damages such as hypertension or kidney diseases was also significant in the PheWAS analysis. When compared to individuals with low RIA PRS (tertile 1, 0.41-9.89), those with high RIA PRS (tertile 3, 13.58-23.16) showed significantly higher odds ratio (OR) of MASLD (OR 1.28, 95 % confidence interval [CI] 1.09-1.49) and cirrhosis (OR 1.49, 95%CI 1.03-2.16). In analyses of two-sample Mendelian randomization, genetically predicted RIA significantly correlated with elevated risks of MASLD and cirrhosis (inverse variance weighted odds ratio [95 % CI]: 1.05 [1.01-1.09]) for MASLD, 1.08 [1.02-1.13] for cirrhosis), meanwhile we observed no significant directional pleiotropy or heterogeneity.

CONCLUSION

Renin-independent aldosteronism is genetically associated with higher risks of MASLD and cirrhosis. Targeted treatment of autonomous aldosterone secretion may alleviate MASLD progression.