The Preventive Value and Potential Mechanisms of Zinc Finger DHHC-Type Containing 7 (ZDHHC7) for Hypertension Based on Pharmacogenomic Mediation Analysis

Abstract Objective To investigate the specific mechanisms by which zinc finger DHHC-type containing 7 (ZDHHC7) regulates immune cells and plasma metabolites to reduce the risk of hypertension. Methods Expression quantitative trait loci (eQTL) data for ZDHHC7 were obtained from the eQTLGen database (n = 26,118), while genome-wide association studies (GWAS) data for hypertension (n = 484,598), immune cells (n = 3658), and plasma metabolites (n = 8192) were extracted from the GWAS Catalog. All datasets were derived from European populations. Five Mendelian randomization (MR) methods, including inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, were used to evaluate causal relationships. Sensitivity analyses were performed using Cochran’s Q test, MR-Egger intercept, leave-one-out analysis, and MR-PRESSO. Statistical power of the MR analysis was assessed via post hoc power calculation. Two-step MR was conducted to evaluate the mediating effects of immune cells and plasma metabolites on the relationship between ZDHHC7 and hypertension risk. Results All 5 MR methods indicated a negative association between ZDHHC7 and hypertension risk (IVW: OR = 0.995, 95% CI, 0.992-0.998, P <.001; MR-Egger: OR = 0.994, 95% CI, 0.989-0.998, P = .014; weighted median: OR = 0.994, 95% CI, 0.991-0.998, P = .004; simple mode: OR = 0.993, 95% CI, 0.987-1.000, P = .049; weighted mode: OR = 0.994, 95% CI, 0.990-0.997, P <.001). The summary-level Mendelian randomization (SMR) analysis yielded consistent results (OR = 0.995, 95% CI, 0.990-0.998, P = .011). Sensitivity analyses showed no significant heterogeneity or bias. The estimated post hoc power was 23.73%. Mediation analysis further revealed that 3 immune cell phenotypes (the proportion of B cell subsets lacking IgD and CD27 markers, expression of CD123 on plasmacytoid dendritic cells, and expression of CD123 on CD62L+ plasmacytoid dendritic cells) and 3 plasma metabolites (1-stearoylphosphatidylinositol, nicotinic acid, and lactate) mediated the relationship between ZDHHC7 and hypertension risk. Conclusion ZDHHC7 may reduce the risk of hypertension by modulating specific immune cells and plasma metabolites.