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Background and Aims: Primary aldosteronism (PA) is an adrenal disorder of autonomous aldosterone secretion which promotes arterial injury. We aimed to explore whether PA is causally associated with lower-extremity arterial disease (LEAD). Methods: We included 39,713 patients with diabetes and 419,312 participants without diabetes from UK Biobank. We derived a polygenic risk score (PRS) for PA based on previous genome-wide association studies (GWAS). Outcomes included LEAD and LEAD related gangrene or amputation. We conducted a two-sample Mendelian randomization analysis for PA and outcomes to explore their potential causal relationship. Results: In whole population, individuals with a higher PA PRS had an increased risk of LEAD. Among patients with diabetes, compared to the subjects in the first tertile of PA PRS, subjects in the third tertile showed a 1.24-fold higher risk of LEAD (OR 1.24, 95% CI 1.03–1.49) and a 2.09-fold higher risk of gangrene (OR 2.09, 95% CI 1.27–3.44), and 1.72-fold higher risk of amputation (OR 1.72, 95% CI 1.10–2.67). Among subjects without diabetes, there was no significant association between PA PRS and LEAD, gangrene or amputation. Two-sample Mendelian randomization analysis indicated that genetically predictors of PA was significantly associated with higher risks of LEAD and gangrene (inverse variance weighted OR 1.20 [95% CI 1.08–1.34]) for LEAD, 1.48 [95% CI 1.28–1.70] for gangrene), with no evidence of significant heterogeneity or directional pleiotropy. Conclusions: Primary aldosteronism is genetically and causally associated with higher risks of LEAD and gangrene, especially among patients with diabetes. Targeting on the autonomous aldosterone secretion may prevent LEAD progression. [ABSTRACT FROM AUTHOR]

Renin-independent aldosteronism (RIA) describes the spectrum of autonomous aldosterone secretion from mild to overt. We aimed to explore whether RIA is causally associated with chronic kidney disease (CKD) in patients with diabetes. We cross-sectionally included 1027, 402 and 39,709 patients with any type of diabetes from cohorts of EIMDS, CONPASS and UK Biobank, respectively. In EIMDS, we defined RIA and renin-dependent aldosteronism based on plasma aldosterone and renin concentrations. We performed captopril challenge test to confirm renin-dependent or independent aldosteronism in CONPASS. In UK Biobank, we generated genetic instruments for RIA based on the genome-wide association studies (GWAS). We extracted the corresponding single nucleotide polymorphisms (SNPs) information from the GWAS data of CKD in diabetes. We harmonized the SNP-RIA and SNP-CKD data to conduct the two-sample Mendelian randomization analyses. In EIMDS and CONPASS, when compared to subjects with normal aldosterone concentration or renin-dependent aldosteronism, participants with RIA had a lower estimated glomerular filtration rate, a higher prevalence of CKD, and a higher multivariate-adjusted odds ratio (OR) of CKD (OR 2.62 [95%CI 1.09–6.32] in EIMDS, and 4.31 [1.39–13.35] in CONPASS). The two-sample Mendelian randomization analysis indicated that RIA was significantly associated with a higher risk of CKD (inverse variance weighted OR 1.10 [95 % CI 1.05–1.14]), with no evidence of significant heterogeneity or substantial directional pleiotropy. Among patients with diabetes, renin-independent aldosteronism is causally associated with a higher risk of CKD. Targeted treatment of autonomous aldosterone secretion may benefit renal function in diabetes. • Diabetic patients with RIA had a higher risk of CKD compared to normal aldosterone or renin-dependent aldosteronism. • Two-sample Mendelian randomization analysis indicated that RIA was causally associated with CKD in diabetic patients. • Targeted treatment of autonomous aldosterone secretion may benefit renal function in diabetic patients. [ABSTRACT FROM AUTHOR]