脂质调节药物靶点与房颤的关联：来自孟德尔随机化研究的证据-现代医学

脂质调节药物靶点与房颤的关联：来自孟德尔随机化研究的证据

单位：郑州市中医院/河南中医药大学附属郑州中医院心血管科, 河南郑州 450000

分类号：R259

出版年·卷·期（页码）：2025·53·第七期（1031-1037）

摘要：

目的：探究脂质调节药物与房颤(atrial fibrillation，AF)之间的因果关系。方法：首先通过两样本孟德尔随机化(Mendelian randomization，MR)分析，探讨总胆固醇(total cholesterol，TC)、总甘油三酯(total triglycerides，TG)、低密度脂蛋白(low-density lipoproteins，LDL)、高密度脂蛋白(high-density lipoproteins，HDL)、载脂蛋白A1和载脂蛋白B与AF之间的因果关联，并进行外部数据验证。药物靶点MR与基于汇总数据的孟德尔随机化(summary data-based Mendelian randomization，SMR)被用来进一步探讨HMGCR、LPL、CETP、LDLR、PCSK9与AF之间的因果关系。中介效应MR分析评估HMGCR通过LDL对AF的影响。结果：两样本的MR分析表明，遗传预测的载脂蛋白A1与AF风险之间存在负相关关系[OR：0.83(95%CI 0.74~0.94)]，TC、TG、LDL、HDL和载脂蛋白B之间未发现显著的因果关联。药物靶点MR分析未能发现HMGCR、LPL、CETP、LDLR、PCSK9与AF之间的显著因果关系。SMR分析显示HMGCR的rs6453133位点与AF风险相关，但中介效应MR分析未表明HMGCR能够通过LDL导致AF。结论：本研究提供了遗传预测的载脂蛋白A1与AF风险之间负相关的证据，而HMGCR基因的rs6453133可能通过调节HMGCR基因位点的表达影响AF的进展，但需要进一步研究来验证这一点。

Objective:To investigate the relationship between lipid-modulating drugs and atrial fibrillation(AF). Methods:A causal association between total cholesterol(TC), total triglycerides(TG), low-density lipoproteins(LDL), high-density lipoproteins(HDL), apolipoprotein A1, and apolipoprotein B with AF was investigated initially using Mendelian randomization(MR). Drug-targeted MR and summary data-based Mendelian randomization(SMR) were used to investigate causal relationships between HMGCR, LPL, CETP, LDLR, PCSK9, and AF. A mediation MR analysis was also performed to assess the effect of HMGCR on AF through LDL. Results: The two MR analysis across the two datasets illustrated an inverse association between genetically predicted apolipoprotein A1 and AF risk[OR: 0.83(95%CI 0.74-0.94)]. No significant causal links were found between TC, TG, LDL, HDL, and apolipoprotein B. An additional drug-targeted MR analysis found no significant causal relationships between HMGCR, LPL, CETP, LDLR, PCSK9. The SMR analysis determined that HMGCR was related to AF risk, whereas the mediation MR analysis did not indicate that HMGCR could cause AF via LDL. Conclusion: This study provides evidence for a negative association between genetically predicted ApoA1 and AF risk, whereas rs6453133 of the HMGCR gene may influence AF progression by modulating expression of the HMGCR locus, which needs further studies to be confirmed.

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