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Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and susceptibility to preterm birth: A case-control study and meta-analysis

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Abstract

Background

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.

Objective

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.

Study design

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).

Results

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).

Conclusions

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.

Introduction

Preterm birth (PTB), defined as birth before the completion of 37 weeks of gestation, is the leading cause of newborn morbidity, mortality, and hospitalization in the first year of life with lifelong consequences for the premature babies and their families [1]. PTB is etiologically complex, with contributions from both the environment and genetics [2, 3]. PTB has a tendency for familial aggregation and higher recurrence in women providing the evidence that genetic factors play a significant risk in this multifactorial disorder [4]. Furthermore, the heritability of PTB, based on twin studies, was estimated at about 30% [3]. Despite the fact that several polymorphisms in various genes have been investigated in association with PTB [5], there is no genetic factor clearly associated with the high risk of PTB. Identifying genetic risk factors in order to elucidate its etiology and to prevent its onset is therefore of major importance.

The angiotensin-converting enzyme (ACE) gene, located on chromosome 17q23, is divided as an insertion/deletion (I/D) polymorphism based on the presence or absence of 287-base pair Alu repetitive sequence in the intron 16 [6]. ACE is a dipeptidyl carboxypeptidase responsible for converting angiotensin I into a biologically active peptide angiotensin II, a potent vasopressor and aldosterone-stimulator that is important in blood pressure regulation, cardiovascular function accommodation, and electrolyte homeostasis [6]. Angiotensin II also inactivates bradykinin, a potent vasodilator. Furthermore, the DD genotype has previously been shown to be a risk factor in pregnancies complicated by pre-eclampsia [7], intrauterine growth restriction (IUGR), and recurrent spontaneous miscarriages [8], all of which have a common factor of deficient placentation. In addition, DD genotype has been reported to possibly influence the regulation of fibrinolytic system and inflammation [9]. The D allele was suggested to be a major factor in the association between low birth weight and high blood pressure levels in children [10]. Moreover, the genes regulating renin-angiotensin system (RAS) have also been implicated in PTB [[11], [12], [13]].

Studies so far have indicated that the D allele and DD genotype have a tendency to increase PTB risk, but the results were inconsistent [14]. Since PTB is a multifactorial disorder, we hypothesized that the D allele of the ACE polymorphism may represent a risk factor that can be reliably detected when comparing a larger number of subjects.

In order to test the genetic association between the ACE I/D polymorphism in intron 16 and PTB, we conducted a case-control association study in Slovenian and Serbian women. Altogether, 375 women were included in the study (217 women with a history of the PTB of unknown etiology and 158 women who experienced full-term pregnancies). In addition, we carried out a meta-analysis aiming to clarify whether the ACE I/D polymorphism is related to PTB risk.

Section snippets

Ethics statement

All participants have provided a written informed consent prior to participation in the study, which has been approved by the Republic of Slovenia National Medical Ethics Committee and by the Serbian Ethics Committee of the Obstetrics and Gynaecology Clinic Narodni Front. Clinical investigations have been conducted according to the principles expressed in the Declaration of Helsinki.

Subjects

The study population consisted of 375 healthy mothers with singleton pregnancies, including 314 from Slovenia and

Case-control study results

No deviation from the HWE was observed for the ACE I/D polymorphism in controls (p = 0.888). Genotypic and allelic comparisons between cases and controls are shown in Table 1. We did not detect any significant association between the ACE I/D polymorphism and risk of PTB in Slovenian and Serbian populations. We found the strongest associations under dominant (DD + ID vs. II: OR = 1.65, 95% CI = 0.98–2.77, p = 0.059) and allelic comparison models (D vs. I: OR = 1.30, 95% CI = 0.97–1.73,

Discussion

In the present study we performed a case-control study of the association of the ACE insertion/deletion polymorphism with PTB and a subsequent meta-analysis of this original dataset with the currently published data. Even though we could not confirm the association of the ACE I/D polymorphism with PTB in our study sample, we could detect a significant association in the pooled analysis when including the data from 3 previously performed studies.

The main reason for this negative result in the

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgment

This study was supported by grant P3-0326 from the Slovenian Research Agency.

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