Association of Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism with Recurrent Pregnancy Loss: a Meta-Analysis of 26 Case-Control Studies

Abstract

Objective Previous studies investigating the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and recurrent pregnancy loss (RPL) risk has provided inconsistent results. The aim of our study was to assess the association between the ACE I/D polymorphism and risk of RPL. Methods All studies published up to January 30, 2018 on the association of ACE I/D polymorphism with RPL were identified by searching the PubMed, Web of Knowledge, and Google scholar databases. Results A total of 26 case-control studies with 3,140 RPL cases and 3,370 controls were included in the meta-analysis. Overall, there was a significant association between ACE I/D polymorphism and RPL risk under the allele model (I versus D: odds ratio [OR] = 0.538, 95% confidence interval [CI] = 0.451–0.643, p ≤ 0.001), the homozygote model (II versus DD: OR = 0.766, 95% CI = 0.598–0.981, p = 0.035) and the recessive model (II versus ID + DD: OR = 0.809, 95% CI = 0.658–0.994, p = 0.044). Subgroup analysis by ethnicity showed that there was a significant association between ACE I/D polymorphism and increased risk of RPL in Caucasian and West-Asian populations, but not in East-Asians. When stratified by number of recurrent miscarriages (RMs), a significant association between ACE I/D polymorphism and increased risk of RPL was detected in the group of studies with ≥ 2 RMs, but not in studies with ≥ 3 RMs. Conclusion The meta-analysis suggests that ACE I/D polymorphism is associated with increased risk of RPL. The ACE I/D polymorphism may be a risk factor for RPL in Caucasian and West-Asian populations, but not in East-Asians.

The Angiotensin-converting Enzyme Insertion/Deletion Polymorphism as a Common Risk Factor for Major Pregnancy Complications

“…The most common and significant DNA polymorphism detected in the ACE gene is the I/D polymorphism (rs4646994) (10,25). The I/D polymorphism is an insertion or deletion of a 287 bp fragment in intron 16 (10,25).…”

“…The most common and significant DNA polymorphism detected in the ACE gene is the I/D polymorphism (rs4646994) (10,25). The I/D polymorphism is an insertion or deletion of a 287 bp fragment in intron 16 (10,25). The D allele is associated with elevated plasma ACE levels and, thus, with enhanced ACE activity (11) More specifically, the homozygotes for the D allele (D/D) tend to have twice higher levels of the encoded enzyme circulating in blood plasma in comparison with individuals homozygous for the I allele (I/I), which is linked to the lowest ACE levels (26).…”

“…Consequently, levels of fibrinolysis are decreased, leading to the conclusion that ACE may act as a hypofibrinolytic factor if its expression is not normally low (6,7). Quite the reverse, the overexpression of PAI-1, due to elevated ACE concentration, may lead to thrombotic incidents (10).…”

“…The etiology of RPL is still unclear since it is a multifactorial disorder affected by the interaction of environmental and genetic factors, such as gene polymorphisms, chromosomal anomalies and, in some cases, by inherited or acquired thrombophilia (10,47,48). Abnormalities in fetal implantation and development, and most importantly in placental and fetal vasculature, may lead to gestational disturbance and eventually miscarriage (47).…”

“…Based on the previously described biological role of RAS in pregnancy and in the light of the close relationship between ACE and plasminogen activator inhibitor-1 (PAI-1), which is crucial for fibrinolysis and embryo implantation (Figure 2), it is not surprising that the ACE I/D polymorphism may be a potential susceptibility factor for RPL (7,10,47,50). The ID and DD genotypes are linked to enhanced ACE levels leading to higher expression of PAI-1.…”