Relationship of obesity, body fat, benign adrenal tumors and the mediating mechanism: a two-step mendelian randomization study.

Background: Benign adrenal tumors comprise the majority of asymptomatic adrenal masses and are often associated with cortisol secretion, which increases the risk of obesity and metabolic syndrome. Hormone secretion by these tumors may confound prevailing epidemiologic findings, and the causal relationships among obesity, body fat, and benign adrenal tumors remain uncertain. Mendelian randomization (MR) uses genetic variation as an instrumental variable to simulate randomized controlled trials, thereby reducing confounding and supporting causal relationships. Therefore, we aim to use MR methods to investigate causal relationships between obesity, body fat, and benign adrenal tumors. And use two-step MR to evaluate potential mediating mechanisms and their mediation proportions.

Method: Single nucleotide polymorphisms significantly associated with obesity, body fat and possible mediators were selected as instrumental variables from published genome-wide association studies (GWAS). GWAS data for benign adrenal tumor cases (n = 1,790) and controls (n = 390,633) were obtained from the Finngen database. Univariable MR analysis was performed to evaluate the causal associations of obesity and body fat with benign adrenal tumors, with obesity and body fat quantified using ten anthropometric indicators. In addition, two-step MR was used to examine four categories of possible mediators (metabolic indicators, hormone indicators, inflammation and oxidation indicators, and diseases) to explore potential mechanisms between obesity, body fat, and benign adrenal tumors and to calculate mediation proportions.

Result: Our results show that all anthropometric indicators are risk factors for benign adrenal tumors (OR range from 1.59 to 2.49 with FDR < 0.05). In addition, two-step MR analysis shows that both total and bioavailable testosterone levels significantly mediate body fat percentage, trunk fat percentage, and trunk fat mass on benign adrenal tumors in women (mediation proportion: 4.07%-15.58%). In addition, bioavailable testosterone levels mediate whole body fat mass (10.95%) and body mass index (17.04%), while total testosterone levels mediate hip circumference (7.27%) in women.

Conclusion: Our study demonstrates that obesity and elevated body fat may serve as risk factors for benign adrenal tumors. Furthermore, we identify the mediating role of total/bioavailable testosterone levels in women, suggesting its potential target for prevention and intervention of benign adrenal tumors in individuals with obesity or high body fat.