Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.
Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Korea.
PLoS One. 2020 Nov 9;15(11):e0241215. doi: 10.1371/journal.pone.0241215. eCollection 2020.
Ritodrine is one of the most commonly used tocolytics in preterm labor, acting as a ß2-adrenergic agonist that reduces intracellular calcium levels and prevents myometrial activation. Ritodrine infusion can result in serious maternal complications, and pulmonary edema is a particular concern among these. The cause of pulmonary edema following ritodrine treatment is multifactorial; however, the contributing genetic factors remain poorly understood. This study investigates the genetic variants associated with ritodrine-induced pulmonary edema.
In this case-control study, 16 patients who developed pulmonary edema during ritodrine infusion [case], and 16 pregnant women who were treated with ritodrine and did not develop pulmonary edema [control] were included. The control pregnant women were selected after matching for plurality and gestational age at the time of tocolytic use. Maternal blood was collected during admission for tocolytic treatment, and whole exome sequencing was performed with the stored blood samples.
Gene-wise variant burden (GVB) analysis resulted in a total of 71 candidate genes by comparing the cumulative effects of multiple coding variants for 19729 protein-coding genes between the patients with pulmonary edema and the matched controls. Subsequent data analysis selected only the statistically significant and deleterious variants compatible with ritodrine-induced pulmonary edema. Two final candidate variants in CPT2 and ADRA1A were confirmed by Sanger sequencing.
We identified new potential variants in genes that play a role in cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) regulation, which supports their putative involvement in the predisposition to ritodrine-induced pulmonary edema in pregnant women.
利托君是治疗早产最常用的保胎药物之一，作为一种β2-肾上腺素能激动剂，它可以降低细胞内钙水平并防止子宫肌激活。利托君输注可导致严重的母体并发症，肺水肿是其中特别关注的问题。利托君治疗后发生肺水肿的原因是多因素的；然而，其遗传因素仍知之甚少。本研究调查了与利托君诱导性肺水肿相关的遗传变异。
在这项病例对照研究中，纳入了 16 名在利托君输注期间发生肺水肿的患者（病例组）和 16 名接受利托君治疗但未发生肺水肿的孕妇（对照组）。对照组孕妇是在多胎和保胎治疗时的妊娠年龄相匹配的情况下选择的。在保胎治疗期间采集母体血液，并对储存的血液样本进行外显子组测序。
通过比较患者与匹配对照组之间 19729 个编码蛋白基因中多个编码变异的累积效应，基因变异负担（GVB）分析总共鉴定出 71 个候选基因。随后的数据分析仅选择了与利托君诱导性肺水肿相容的统计学意义显著和有害的变异。CPT2 和 ADRA1A 中的两个最终候选变异通过 Sanger 测序得到了确认。
我们在参与环腺苷酸（cAMP）/蛋白激酶 A（PKA）调节的基因中发现了新的潜在变异，这支持了它们在孕妇中易患利托君诱导性肺水肿中的潜在作用。
