磷酸二酯酶抑制剂对妊娠期高血压疾病和胎儿生长受限的治疗作用：一项药物靶向孟德尔随机化研究
Therapeutic Effects of Phosphodiesterase Inhibitors on Hypertensive Disorders in Pregnancy and Fetal Growth Restriction: A Drug Targeted Mendelian Randomization Study.
摘要(中文译文)
磷酸二酯酶（PDEs）因其与多种病理和生理过程密切相关而被认为是具有前景的药物靶点。本研究旨在探讨PDE抑制剂与妊娠期高血压疾病（HDP）及胎儿生长受限（FGR）之间的因果关系。我们使用与PDEs相关的表达数量性状位点（eQTLs）作为PDE基因表达水平的替代指标，通过药物靶点方法进行了单样本孟德尔随机化（SMR）分析和双样本孟德尔随机化验证。SMR分析显示，PDE4B、PDE5A、PDE8A和PDE9A与妊娠结局相关。双样本孟德尔随机化验证发现，血液中PDE5A与FGR的发生呈负相关（OR = 0.91，CI = 0.81-1.00，p = 0.045），而PDE4B是妊娠期高血压（GH）的危险因素（OR = 1.24，95% CI = 1.09-1.39，p = 0.006）。我们再次使用与PDE5A相关的蛋白质数量性状位点（pQTLs）作为PDE5A蛋白质水平的替代指标进行SMR分析，结果显示PDE5A与HDP或FGR之间无显著关联。采用两步孟德尔随机化方法进一步验证PDE4B与GH之间的因果关系，发现PDE4B通过多种代谢因素促进GH的发生。我们的孟德尔随机化结果将PDE4B而非PDE5A列为GH的因果驱动因素，为在妊娠期重新定位选择性PDE4B抑制剂提供了遗传学依据。PDE5A对胎儿生长的保护性信号需要组织水平的验证，并在任何临床再评估之前谨慎进行剂量探索。PDE5A不是HDP和FGR的潜在治疗靶点，而PDE4B与GH的发生密切相关。这提示PDE4B抑制剂可能对GH具有治疗潜力，并为HDP和FGR的治疗提供了重要参考。
Abstract
Phosphodiesterases (PDEs) are considered promising drug targets due to their close association with various pathological and physiological processes. We aimed to investigate the causal relationship between PDE inhibitors and hypertensive disorders of pregnancy (HDP) and fetal growth restriction (FGR). We used expression quantitative trait loci (eQTLs) related to PDEs as surrogate indicators of PDE gene expression levels and conducted single-sample Mendelian randomization (SMR) analysis and two-sample MR validation through the pharmacological target. SMR analysis showed that PDE4B, PDE5A, PDE8A, and PDE9A were associated with pregnancy outcomes. Two-sample MR validation revealed that PDE5A in blood was negatively correlated with the occurrence of FGR (OR = 0.91, CI = 0.81-1.00, p = 0.045), while PDE4B was a risk factor for gestational hypertension (GH) (OR = 1.24, 95% CI = 1.09-1.39, p = 0.006). We performed SMR analysis again using protein quantitative trait loci (pQTLs) related to PDE5A as a surrogate for PDE5A protein levels, and the results showed no significant association between PDE5A and HDP or FGR. Further validation of the causal relationship between PDE4B and GH using a two-step MR approach revealed that PDE4B promotes the occurrence of GH through multiple metabolic factors. Our MR results prioritize PDE4B, but not PDE5A, as a causal driver of GH, offering genetically anchored justification for repositioning selective PDE4B inhibitors in pregnancy. Protective signals for PDE5A on fetal growth require tissue-level confirmation and cautious dose-finding before any clinical re-evaluation. PDE5A is not a potential therapeutic target for HDP and FGR, while PDE4B is closely related to the occurrence of GH. This suggests that PDE4B inhibitors may have therapeutic potential for GH and provides an important reference for the treatment of HDP and FGR.
如何引用
AMA
Dandan Xia, Siyu Li, Wenjie Liu, Yuhui Zhang, Chenying Zhang, Guangtong She, et al. Therapeutic Effects of Phosphodiesterase Inhibitors on Hypertensive Disorders in Pregnancy and Fetal Growth Restriction: A Drug Targeted Mendelian Randomization Study.. Current medicinal chemistry. 2026; doi:10.2174/0109298673448115260306053602.
APA
Dandan Xia, Siyu Li, Wenjie Liu, Yuhui Zhang, Chenying Zhang, Guangtong She, et al (2026). Therapeutic Effects of Phosphodiesterase Inhibitors on Hypertensive Disorders in Pregnancy and Fetal Growth Restriction: A Drug Targeted Mendelian Randomization Study.. Current medicinal chemistry. https://doi.org/10.2174/0109298673448115260306053602
GB/T 7714
Dandan Xia, Siyu Li, Wenjie Liu, Yuhui Zhang, Chenying Zhang, Guangtong She, et al. Therapeutic Effects of Phosphodiesterase Inhibitors on Hypertensive Disorders in Pregnancy and Fetal Growth Restriction: A Drug Targeted Mendelian Randomization Study.[J]. Current medicinal chemistry, 2026 doi:10.2174/0109298673448115260306053602.
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