基于药物基因组中介分析研究棕榈酰转移酶7对高血压的预防潜力及潜在机制

The preventive value and potential mechanisms of zinc finger DHHC-type containing 7 (ZDHHC7) for hypertension based on pharmacogenomic mediation analysis

    摘要
  • 摘要:
    目的  探讨棕榈酰转移酶7（ZDHHC7）调控免疫细胞与血浆代谢物降低高血压风险的具体机制。
    方法  从eQTLGen数据库提取ZDHHC7的表达数量性状基因座（eQTL）数据（n=26 118），从GWAS Catalog数据库提取高血压（n=484 598）、免疫细胞（n=3 658）及血浆代谢物（n=8 192）的全基因组关联分析（GWAS）数据，数据均来源于欧洲人口，采用五种孟德尔随机化（MR）方法逆方差加权（IVW）、MR-Egger回归、加权中位数、简单模式、加权模式评估其因果关系，应用Cochran’s Q、MR-Egger截距、留一法、MR-PRESSO进行敏感性分析，通过事后效应计算评估MR分析的统计效能。通过两步MR法评估免疫细胞与血浆代谢物在ZDHHC7与高血压风险中的中介效应。
    结果 五种MR方法均显示ZDHHC7与高血压风险呈负相关（IVW法：OR=0.995，95%CI 0.992～0.998，P＜0.001；MR-Egger法：OR=0.994，95%CI 0.989～0.998，P=0.014；加权中位数法：OR=0.994，95%CI 0.991～0.998，P=0.004；简单模型：OR=0.993，95%CI 0.987～1.000，P=0.049；加权模型：OR=0.994，95%CI 0.990～0.997，P＜0.001）。汇总数据的孟德尔随机化（SMR）分析结果具有一致性（OR=0.995，95%CI 0.990～0.998，P=0.011）。敏感性分析未发现显著的异质性或偏倚，事后功效估算为23.73%。中介分析进一步揭示3种免疫细胞表型（缺乏IgD和CD27标记的B细胞亚群的比例、浆细胞样树突状细胞上的CD123是否表达、CD62L+浆细胞样树突状细胞上的CD123是否表达）和3种血浆代谢物（1-硬脂酰基磷脂酰肌醇、尼克酸、乳酸）在ZDHHC7与高血压风险间起到中介作用。
    结论 ZDHHC7具有调控特定免疫细胞与血浆代谢物，从而降低高血压风险的潜在作用。

     

    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=3 658), and plasma metabolites (n=8 192) 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 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 five MR methods indicated a negative association between ZDHHC7 and hypertension risk (IVW: OR=0.995, 95%CI 0.992–0.998, P＜0.001; MR-Egger: OR=0.994, 95%CI 0.989–0.998, P=0.014; weighted median: OR=0.994, 95%CI 0.991–0.998, P=0.004; simple mode: OR=0.993, 95%CI 0.987–1.000, P=0.049; weighted mode: OR=0.994, 95%CI 0.990–0.997, P＜0.001). The summary-level Mendelian randomization (SMR) analysis yielded consistent results (OR=0.995, 95%CI 0.990–0.998, P=0.011). Sensitivity analyses showed no significant heterogeneity or bias. The estimated post hoc power was 23.73%. Mediation analysis further revealed that three 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 three 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.

     

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