Significant association between angiotensin-converting enzyme gene insertion/deletion polymorphism and risk of recurrent miscarriage: A systematic review and meta-analysis

Abstract

Background

Many studies have investigated the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and risk of recurrent miscarriage, but the impact is unclear due to inconsistencies among those studies. This study aimed to quantify the strength of the association between ACE I/D polymorphism and recurrent miscarriage risk by performing a systematic review and meta-analysis.

Design and Methods

We searched PubMed, Embase, Web of Science, and Wanfang Medicine databases for eligible articles relating the association between ACE I/D polymorphism and risk of recurrent miscarriage in humans. We estimated the summary odds ratios (ORs) with their 95% confidence intervals (95% CIs) to assess the association.

Results

Eleven studies with a total of 3357 individuals were included in this meta-analysis. Compared to the ACE II genotype, DD and ID were both associated with increased risk of recurrent miscarriage (OR _{DD versus II} = 1.81, 95% CI 1.23–2.66, P = 0.003; OR _{ID versus II} = 1.50, 95% CI 1.25–1.80, P < 0.001). Sensitivity analyses further confirmed the association above. No evidence of publication bias was observed.

Conclusion

Meta-analyses of available data show a significant association between ACE I/D polymorphism and recurrent miscarriage risk, and the ACE polymorphic D allele contributes to increased risk of recurrent miscarriage.

Introduction

Recurrent miscarriage, defined as 2 or more spontaneous abortions, affects up to 5% of reproductively active couples and an even higher proportion of women 35 years of age and older [1]. In addition, epidemiological investigations have demonstrated that the frequency of subsequent pregnancy loss is over 24% after two pregnancy losses, 30% after three and 40% after four successive pregnancy losses [2]. The cause of recurrent miscarriage is multifactorial, and several factors have been identified as being related to recurrent miscarriage including uterine anomaly, chromosomal abnormalities, endocrine dysfunction, inherited thrombophilias, immune disorders, lifestyle factors, and maternal infections [3], [4]. Acquired and inherited thrombophilia is an important research avenue in the recurrent miscarriage field, and women with thrombophilias may have excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency, thus having an increased risk of recurrent miscarriage [5], [6], [7]. However, the etiology of most recurrent miscarriages is still unclear, and, genetic polymorphisms have been proposed as susceptibility factors in patients with recurrent miscarriage [1], [3].

A normal pregnancy depends on adequate placental circulation and fetal vasculature. The development of a normal functioning vascular network requires cooperation between different cell types and various growth factors in the processes of implantation, embryo development, and placentation. Abnormalities of placental vasculature may result in several gestational complications including pregnancy loss [3], [4]. Several gene polymorphisms affecting placental vasculature and circulation, including Factor V Leiden, prothrombin G20210A mutation, factor XII deficiency, and eNOS Glu298Asp, have been suggested to be associated with increased risk of recurrent miscarriage [5], [6], [8], [9], [10]. Angiotensin-converting enzyme (ACE) also has an important impact on vascular structure and the function of placenta, and the abnormalities of ACE may result in fetal loss or recurrent miscarriage [11], [12], [13]. The human ACE gene is located on chromosome 17q23. The ACE gene was shown to be characterized by an insertion/deletion polymorphism based on the presence (insertion [I]) or absence (deletion [D]) within intron 16 of a 287-base pair alu repeat sequence, resulting in three genotypes (DD and II homozygotes and ID heterozygotes) [14], [15]. Previous studies have suggested that ACE I/D polymorphism is associated with increased risks of thrombotic disorders, such as venous thromboembolism, stroke and coronary artery disease [16], [17], [18]. Since the modified expression of ACE may result in pregnancy loss, the ACE I/D polymorphism may be a susceptibility factor that increases the risk of recurrent miscarriage [11], [12], [15], [19]. Numerous studies have investigated the relationship between ACE I/D polymorphism and recurrent miscarriage risk, but the available evidence from those studies is weak, owing to the sparseness of data and conflicting results [20], [21], [22], [23], [24], [25], [26], [27], [28]. Each of these studies involved few cases and controls and failed to confirm a consistent association. Furthermore, those studies varied markedly by including different populations, sampling strategies, and genotyping procedures. To shed some light on these contradictory results and to decrease the uncertainty of the estimated risk, we presented the results of a meta-analysis of published data investigating the association between ACE I/D polymorphism and recurrent miscarriage risk.