College of Pharmacy and Division of Life & Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
Department of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, 05030, South Korea.
Eur J Clin Pharmacol. 2019 Oct;75(10):1379-1386. doi: 10.1007/s00228-019-02719-9. Epub 2019 Jul 19.
Phosphodiesterase (PDE) terminates the signaling pathway of myometrial relaxation by degradating cAMP to the inactive 5'-AMP. The PDE4 family is one of the most predominant PDE families that display high affinity to cAMP. The objective of this study was to evaluate the effects of PDE4 gene polymorphisms on tocolytic effects and adverse drug events (ADEs) of ritodrine therapy in patients with preterm labor.
A total of 170 preterm labor patients were included in this study. To elucidate the effects of genetic polymorphisms on the inter-individual variability of ritodrine efficacy and ADEs, 8 single nucleotide polymorphisms (SNPs) were genotyped: PDE4D (rs1544791, rs983280, rs1504982, rs10940648, rs829259) and PDE4B2 (rs598961, rs2180335, and rs17128809). Additionally, rs1042719 of the ADRB2 gene was included for multivariate analysis. The primary endpoint of this prospective study was the time to delivery (hr). The secondary endpoint was ritodrine-induced ADEs.
The mutant-type homozygote carriers of PDE4B2 rs598961 polymorphism showed shorter median time to delivery than those with other genotypes (adjusted hazard ratio 1.6, 95% confidence interval 1.0 to 2.4, P = 0.035). On the other hand, patients with wild-type homozygotes of PDE4B2 rs17128809 showed 2.6~2.9 times higher ADEs compared to those with other genotypes. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery, whereas height, weight, and BSA were significant factors for ritodrine-induced ADEs after adjusting other factors.
This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to β2-adrenergic receptor targeted therapy in patients with preterm labor.
磷酸二酯酶（PDE）通过将 cAMP 降解为无活性的 5'-AMP 来终止子宫平滑肌松弛的信号通路。PDE4 家族是对 cAMP 具有高亲和力的最主要的 PDE 家族之一。本研究的目的是评估 PDE4 基因多态性对早产患者利托君治疗的保胎作用和药物不良事件（ADE）的影响。
本研究共纳入 170 例早产患者。为了阐明遗传多态性对利托君疗效和 ADE 个体间变异性的影响，对 8 个单核苷酸多态性（SNP）进行了基因分型：PDE4D（rs1544791、rs983280、rs1504982、rs10940648、rs829259）和 PDE4B2（rs598961、rs2180335 和 rs17128809）。此外，还对 ADRB2 基因的 rs1042719 进行了多变量分析。这项前瞻性研究的主要终点是分娩时间（小时）。次要终点是利托君引起的 ADE。
PDE4B2 rs598961 多态性的突变型纯合子携带者的中位分娩时间短于其他基因型（校正危险比 1.6，95%置信区间 1.0 至 2.4，P=0.035）。另一方面，PDE4B2 rs17128809 野生型纯合子的患者比其他基因型的患者发生 ADE 的风险高 2.6 至 2.9 倍。在人口统计学特征中，药物治疗开始时的孕周和改良 Bishop 评分是分娩时间的显著因素，而身高、体重和 BSA 是调整其他因素后利托君引起的 ADE 的显著因素。
这项药物基因组学研究表明，PDE4 遗传多态性影响早产患者β2-肾上腺素能受体靶向治疗的个体易感性。
