Association between Magnesium Depletion Score and Hypertension: Insights from a Large-Scale Population-Based Study and Bioinformatics Analysis.

Magnesium is an essential macro-mineral that plays a vital role in cardiovascular health. The magnesium depletion score (MDS) has recently been proposed as a composite indicator to assess magnesium status. Although previous studies have linked higher MDS values to cardiovascular and all-cause mortality, evidence regarding its association with hypertension remains limited in large, representative populations. This study aimed to examine the relationship between MDS and hypertension risk and to explore potential molecular mechanisms through integrative bioinformatics analysis. We analyzed data from a large population-based cross-sectional survey. Multivariable logistic regression and restricted cubic spline (RCS) analyses were used to evaluate the association and dose-response relationship between MDS and hypertension. Mediation analysis was conducted to assess the indirect role of metabolic factors. Gene-based bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and disease-gene association analyses, were performed to identify molecular pathways shared among magnesium, hypertension, and diabetes. Higher MDS levels were significantly and independently associated with an increased risk of hypertension across all models. ROC analysis showed that the combination of MDS with other clinical indicators exhibited strong predictive performance (AUC = 0.84). RCS analysis revealed a nonlinear association, with hypertension risk sharply increasing when MDS exceeded 1.59. Mediation analysis indicated that diabetes, hyperlipidemia, and metabolic syndrome did not mediate this relationship. Gene-based integrative analysis identified 1,193 overlapping genes shared between magnesium ion and hypertension, primarily involved in vascular regulation, oxidative stress response, endothelial signaling, and extracellular communication. These genes were significantly enriched in cAMP signaling, AGE-RAGE signaling in diabetic complications, HIF-1 signaling, platelet activation, integrin-mediated interactions, and GPCR-related pathways, suggesting that magnesium deficiency may influence hypertension through vascular remodeling, inflammation, and impaired nitric oxide signaling. Magnesium depletion is strongly associated with hypertension and may contribute to its pathogenesis through coordinated genetic and molecular pathways related to vascular tone, oxidative stress, and inflammatory signaling. Integrating population-based epidemiologic and bioinformatics analyses provides novel mechanistic insight into the link between magnesium status and hypertension.