Hočevar Keli, Peterlin Ana, Jovanović Ana Mitrović, Božović Aleksandra, Ristanović Momčilo, Tul Nataša, Peterlin Borut
Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Clinic of Obstetrics and Gynecology "Narodni Front", Belgrade, Serbia.
Eur J Obstet Gynecol Reprod Biol. 2018 Dec;231:122-128. doi: 10.1016/j.ejogrb.2018.09.019. Epub 2018 Sep 11.
Preterm birth is the largest contributor to newborn mortality, morbidity, and hospitalization in the first year of life worldwide. Previous studies have suggested the importance of genetic variation in the angiotensin-converting enzyme gene, including the angiotensin-converting enzyme gene insertion/deletion polymorphism, in association with preterm birth. The angiotensin-converting enzyme is a key component of the renin-angiotensin system that is involved in blood pressure homeostasis during pregnancy and also affects risk factors of preterm birth, including the regulation of fibrinolytic system, uteroplacental circulation, vascularization of the placenta, and inflammation.
The results of previous studies investigating the association between the insertion/deletion polymorphism and susceptibility to preterm birth have been inconsistent, therefore, we have performed a case-control study and conducted a meta-analysis of related studies to clarify this association.
In a case-control genetic association study, performed on 217 women with a history of preterm birth and 158 women who experienced full-term pregnancy, the significances of associations between allelic and genotype frequencies and preterm birth were determined using Chi-square tests. Following the case-control study, PubMed, Scopus, Google Scholar, and HugeNavigator databases were systematically searched to identify relevant studies. Altogether, four eligible studies involving 369 cases and 559 controls were included in the meta-analysis. The strength of the association between the angiotensin-converting enzyme gene insertion/deletion polymorphism for preterm birth was estimated by odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs), using a fixed-effects model (Mantel-Haenszel method).
In our case-control study we did not detect a significant association of angiotensin-converting enzyme insertion/deletion alleles and genotypes with preterm birth. The results of the meta-analysis showed a significant association between the angiotensin-converting enzyme gene insertion/deletion and the risk of preterm birth under allelic, dominant, and recessive comparison genetic models (D vs. I: OR = 1.35, 95% CI = 1.11-1.65, p = 0.0033; DD + ID vs. II: OR = 1.52, 95% CI = 1.08-2.15, p = 0.0161; DD vs. ID + II: OR = 1.48, 95% CI = 1.07-2.04, p = 0.0184).
The present meta-analysis suggests that the insertion/deletion polymorphism of the angiotensin-converting enzyme gene in mothers might be associated with preterm birth, however, further well-designed large replication studies involving various ethnicities are needed to confirm this association.
早产是全球新生儿死亡、发病及出生后第一年住院的最大原因。既往研究提示血管紧张素转换酶基因的遗传变异，包括血管紧张素转换酶基因插入/缺失多态性，与早产相关。血管紧张素转换酶是肾素-血管紧张素系统的关键组成部分，参与孕期血压稳态调节，还影响早产的危险因素，包括纤维蛋白溶解系统调节、子宫胎盘循环、胎盘血管形成及炎症。
既往研究探讨插入/缺失多态性与早产易感性的关联结果不一致，因此，我们开展了一项病例对照研究并对相关研究进行荟萃分析以明确这种关联。
在一项病例对照基因关联研究中，对217例有早产史的女性和158例足月妊娠女性进行研究，采用卡方检验确定等位基因和基因型频率与早产之间关联的显著性。病例对照研究之后，系统检索PubMed、Scopus、谷歌学术和HugeNavigator数据库以识别相关研究。荟萃分析共纳入4项符合条件的研究，涉及369例病例和559例对照。采用固定效应模型（Mantel-Haenszel法）通过比值比（OR）及相应的95%置信区间（95%CI）估计血管紧张素转换酶基因插入/缺失多态性与早产之间关联的强度。
在我们的病例对照研究中，未检测到血管紧张素转换酶插入/缺失等位基因和基因型与早产之间存在显著关联。荟萃分析结果显示，在等位基因、显性和隐性比较遗传模型下，血管紧张素转换酶基因插入/缺失与早产风险之间存在显著关联（D与I比较：OR = 1.35，95%CI = 1.11 - 1.65，p = 0.0033；DD + ID与II比较：OR = 1.52，95%CI = 1.08 - 2.15，p = 0.0161；DD与ID + II比较：OR = 1.48，95%CI = 1.07 - 2.04，p = 0.0184）。
本荟萃分析提示母亲血管紧张素转换酶基因的插入/缺失多态性可能与早产相关，然而，需要进一步开展设计良好的涉及不同种族的大型重复研究来证实这种关联。
