Evaluating the Causal Roles of Matrix Metalloproteinases in Metabolic Syndrome: A Mendelian Randomization Study Highlighting MMP12 in Blood Pressure Regulation.

PURPOSE: This study aims to investigate whether matrix metalloproteinases (MMPs) are associated with the risk of metabolic syndrome (MetS) and its components.

METHODS

We conducted a two-sample Mendelian randomization (MR) study by using 9 types of MMPs as exposures and MetS and its components (waist circumference, essential hypertension, fasting blood glucose [FBG], high-density lipoprotein [HDL] cholesterol, and triglycerides) as outcomes. The genome-wide association study summary data of exposure and outcome were both obtained from publicly published research. Four MR analytical methods, including inverse variance weighted, MR-Egger, weighted median, and weighted mode, were applied to analyze the causality between exposure and outcome, in which IVW was employed as the primary analytical method. MR-Egger, Cochran's Q, leave-one-out (LOO), and MR pleiotropy residual sum and outlier (MR-PRESSO) were used to assess the reliability of the results of the MR analysis.

RESULTS

Genetically determined MMP12 showed significant negative associations to the risk of essential hypertension (OR = 0.996, 95% CI: 0.993-0.998, p = 0.001). Results that were analyzed with the MR-Egger, weighted median, and weight mode were consistent with those analyzed with IVW. Although MMP12 may have a suggestive protective effect on FBG levels (OR = 0.993, 95% CI: 0.986-1, p = 0.049), this finding may be affected by potential horizontal pleiotropy and requires further validation. No causal associations were identified between other MMPs and the risk of MetS or its components.

CONCLUSIONS

This MR analysis provides evidence of causal links between MMP12 and the risk of essential hypertension, indicating that MMP12 might inform early risk stratification for specific cardiometabolic components (e.g., essential hypertension), rather than serving as a diagnostic biomarker for the composite metabolic syndrome.