Exploring the causal relationship between matrix metalloproteinases and adrenocortical carcinoma: A Mendelian randomization study

The precise relationship between adrenocortical carcinoma (ACC) and matrix metalloproteinases (MMP) remains unclear. In this 2-sample Mendelian randomization (MR) study, exposure data regarding serum MMP levels were obtained from genome-wide association studies that included 21,758 individuals across 13 cohorts of European ancestry. The outcome data related to ACC were sourced from the FinnGen research project. The inverse-variance weighting method was employed as the primary analytical approach and was further verified using a variety of statistical techniques, including MR-Egger, weighted median, weighted mode, Bayesian weighted Mendelian randomization, constrained maximum likelihood, contamination mixture method and debiased inverse-variance weighted method. A Steiger directionality test was applied to avoid a reverse causation association. To assess pleiotropy and heterogeneity, we conducted the MR-Egger intercept test, Cochran Q test, and leave-one-out analyses. Using the IVW and Bonferroni-corrected approach, we observed that elevated serum levels of MMP-12 were associated with a reduced risk of ACC, with an odds ratio of 0.699 (95% confidence interval: 0.544-0.895; P = .005). Sensitivity analyses indicated the absence of significant heterogeneity and pleiotropy within our study. Additionally, the Steiger directionality test did not detect a significant reverse causation effect. The causal relationship between MMP-12 levels and ACC could have significant implications for the diagnostic and therapeutic approaches employed in the management of ACC.