Causal effects of primary aldosteronism on inflammation and bone density: evidence from Mendelian randomization, animal, and clinical studies.

BACKGROUND: Studies on the pro-inflammatory effects of primary aldosteronism (PA) in humans have largely relied on measurements of circulating inflammatory biomarkers and are mostly observational in nature, making it difficult to establish a causal relationship between PA and inflammatory responses. In addition, the association between PA and bone mineral density (BMD) remains controversial and warrants further investigation. OBJECTIVE: This study aimed to evaluate the causal effects of PA on circulating inflammatory proteins and bone mineral density. METHODS: We performed a Mendelian randomization (MR) analysis to assess the causal relationships between PA and 91 circulating inflammatory proteins, as well as BMD at four anatomical sites. The findings were further validated using a rat model and clinical data. RESULTS: MR analysis revealed significant inverse causal associations between PA and the circulating levels of interleukin-10 receptor subunit beta (IL-10RB) and hepatocyte growth factor (HGF). These findings were further supported by the rat model results, in which serum IL-10RB (2.10 ± 1.18 ng/mL) and HGF (1120.95 ± 144.33 pg/mL) levels in the Aldo-salt group were significantly lower than those in both the Aldo-salt-Epl group (4.80 ± 1.40 ng/mL and 1434.74 ± 192.45 pg/mL, respectively) and the control group (5.07 ± 0.79 ng/mL and 1540.42 ± 316.32 pg/mL, respectively) (P < 0.05). Consistently, clinical data showed that patients with PA had significantly lower serum IL-10Rb and HGF levels compared to those with essential hypertension (EH) (1146.20 ± 178.23 vs. 1660.49 ± 238.44 pg/mL and 1082.93 ± 231.47 vs. 1935.18 ± 296.44 pg/mL, respectively; P < 0.001 for both). Notably, MR analysis did not identify any significant causal associations between PA and bone mineral density at the total body, forearm, femoral neck, or lumbar spine. CONCLUSION: This study is the first to demonstrate a causal relationship between PA and reduced circulating levels of IL-10RB and HGF, suggesting that PA may promote disease progression by impairing anti-inflammatory defenses and providing new insights for diagnostic and therapeutic strategies targeting inflammation-related pathways.