Review

A meta-analysis of the association of the ACE I/D and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss in Iranian women: Are the investigations adequate?

10.4274/tjod.galenos.2021.58997

  • Seyed Alireza Dastgheib
  • Mojgan Karimi-Zarchi
  • Reza Bahrami
  • Razieh Sadat Tabatabaei
  • Atiyeh Javaheri
  • Mahmood Noorishadkam
  • Seyed Reza Mirjalili
  • Hossein Neamatzadeh

Received Date: 16.09.2020 Accepted Date: 07.04.2021 Turk J Obstet Gynecol 2021;18(2):139-150 PMID: 34083696

The associations of ACE I/D and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss (RPL) in Iranian women have yielded controversial results. Thus, we conducted a meta-analysis to obtain more certain results. A comprehensive literature search was performed in the PubMed, Web of Sciences, Scopus, MedRxiv, SID, and CNKI databases up to January 1st, 2021, using the appropriate terms. All case-control studies were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of associations. A total of 14 studies including eight studies with 783 patients and 761 healthy subjects on ACE I/D and six studies with 1.155 patients and 699 healthy subjects on PAI-1 4G/5G were included. Combined data revealed that ACE I/D polymorphism was significantly associated with RPL risk in Iranian women under three models i.e., allele [OR=0.744, 95% CI: (0.640-0.864); p≤0.001], dominant [OR=0.774, 95% CI: (0.601-0.996); p=0.047], and recessive [OR=0.767, 95% CI: (0.611-0.963); p=0.022]. Moreover, the pooled data showed a significant association between the PAI-1 4G/5G polymorphism and RPL risk under all five models i.e., allele [OR=2.352, 95% CI: (1.623-3.408); p≤0.001], heterozygote [OR=8.364, 95% CI: (4.744-14.756); p≤0.001), homozygote [OR=2.192, 95% CI: (1.093-4.394); p=0.027), dominant [OR=2.354, 95% CI: (1.309-4.235); p=0.004], and recessive [OR=5.208, 95% CI: (3.005-9.025); p≤0.001]. Stratification analysis revealed that these polymorphisms were associated with RPL risk by the number of miscarriages. Our pooled data indicated that ACE I/D and PAI-1 4G/5G polymorphisms were significantly associated with an increased risk of RPL in Iranian women. These significant findings showed that the investigation might be adequate for ACE I/D and PAI-1 4G/5G polymorphisms in the Iranian population.

Keywords: Pregnancy loss, miscarriage, thrombophilia, plasminogen activator inhibitor-1, angiotensin-I-converting enzyme, polymorphism

Introduction

Recurrent pregnancy loss (RPL) is one of the main public health issues with a rate of 5% among women of reproductive age(1,2). RPL is defined as the loss of three or more successive pregnancies before viability and includes all pregnancy losses from the time of conception until 24 weeks of gestation(3,4,5). The most commonly cited causes of miscarriage are structural chromosome abnormalities of one of the partners, uterine abnormalities, elevated random levels of homocysteine, and antiphospholipid syndrome(6,7). Thrombophilia is described as a susceptibility to arterial or venous thrombotic complications due to hemostatic system defects, which may be acquired, like the antiphospholipid syndrome, or inherited(8,9). Adverse pregnancy outcomes, such as pregnancy failure (i.e. sporadic and RPL, late fetal loss), pre-eclampsia, and HELLP syndrome, are associated with thrombotic mechanisms and thrombophilia(10). Thrombotic disorders are detectable in 40-50% of RPL cases(11). It has been presumed that the etiology of RPL is associated with factors involved in fibrinolysis and coagulation(3,12). In the past two decades, several investigators suggested that thrombophilia had an impact on susceptibility to RPL(13,14,15). Thus, genotyping of genetic variants at thrombophilic genes is useful to describe the etiology of RPL, and improvement our knowledge about the nature of this disease(16).

Currently, there are a limited number of genetic variants as independent risk factors for venous thromboembolism in women with RPL(17). There is growing evidence of a causal relationship of genetic variations at plasminogen activator inhibitor-1 (PAI-1) and angiotensin-converting enzyme (ACE) genes with RPL in different populations(3,18). PAI-1, a 52 kDa glycoprotein belonging to the serine proteinase inhibitor superfamily, is the principal inhibitor of tissue and urinary plasminogen activators(3,19,20). PAI-1 is involved in various physiologic functions and associated with many diseases(21,22,23). The most commonly studied functional variant in the PAI-1 gene is the 4G/5G polymorphism, which is characterized by a single guanosine nucleotide insertion/deletion variation at -675 bp to the transcription start site of the PAI-1 gene(24,25). Moreover, ACE or kininase II, is a dipeptidyl carboxypeptidase that plays an important role in regulating blood pressure and electrolyte balance(26,27). The most widely studied polymorphism of ACE is an insertion/deletion (I/D), which is characterized by insertion or deletion of a 287-non-coding base pair Alu repeat sequence(28,29).

RPL is one of the main reproductive health issues in Iran(30,31). However, there is no consensus regarding the frequency of RPL in Iranian women. In the past decade, several molecular studies have evaluated the association of ACE I/D and PAI-1 4G/5G polymorphisms with RPL risk in Iran(3,18). Nevertheless, their results were inconsistent and inconclusive. Moreover, the findings provided limited evidence due to relatively small sample sizes and might have been underpowered to estimate the risk. Thus, meta-analysis is a standardized approach to combine the results of different studies on ACE I/D and PAI-1 4G/5G polymorphisms to provide more reliable conclusions. Therefore, we conducted this meta-analysis to obtain a more precise estimation on the association of ACE I/D and PAI-1 4G/5G polymorphisms with RPL risk in Iranian women from all eligible case-control studies published in English and Farsi.


Materials and Methods


Search Strategy

We performed a comprehensive search on the United States National Library of Medicine’s PubMed, Scopus, EMBASE, Web of Knowledge, MedRxiv, Cochrane Library, Google Scholar, Scientific Information Database, WanFang, VIP, Chinese Biomedical Database, Scientific Electronic Library Online and China National Knowledge Infrastructure database to find all relevant publications on the association of ACE I/D and PAI-1 4G/5G polymorphisms with RPL in Iranian women up till January 1st, 2021. The following keywords and terms were used for the search: (“Pregnancy Loss” OR “RPL” OR “Recurrent Pregnancy Loss” OR “Recurrent Miscarriage” OR “recurrent spontaneous abortion” OR “Idiopathic/Unexplained Recurrent Pregnancy Loss”) AND (“Angiotensin-Converting Enzyme” OR “ACE” OR “SERPINE1”) AND (“Insertion/Deletion Polymorphism” OR “ACE I/D” OR “rs4646994”) AND (“Plasminogen Activator Inhibitor-1” OR “PAI-1”) AND (“4G/5G” OR “rs1799889”) AND (“Gene” OR “Genotype” OR “Allele” OR “Polymorphism” OR “Single nucleotide polymorphisms” OR “SNP” OR “Variation” OR “Mutation”). Articles were limited to the English and Farsi languages. Additionally, the reference lists of each eligible study, previous meta-analyses, and review articles were manually checked to find more relevant publications.


Inclusion and Exclusion Criteria

The criteria employed to retrieve publications for this meta-analysis were as follows: (1) studies with case-control or cohort design; (2) studies con­ducted among Iranian populations; (3) studies that evaluated the association of ACE I/D and PAI-1 4G/5G polymorphisms with RPL; (4) studies that provided sufficient data on the geno­type frequencies of the polymorphisms to calculate the pooled odds ratio (OR) with corresponding 95% confidence interval (CI). The exclusion criteria were as follows: (1) studies not relevant to RPL; (2) case-only studies or no controls; (3) linkage studies and family-based studies (twins and sibling); (4) duplicate studies and incomplete data; (5) abstracts, posters, presentations, letters, case reports, case series, comments, conference editorials, reviews and previous meta-analyses; and (6) unpublished data and studies with­out extractable data.


Data Extraction

Data were carefully extracted from all eligible studies independently by two authors according to the criteria listed above. Then, to minimize bias and to improve the reliability of the data, the authors checked all potentially relevant studies independently and reached a consensus or a third author was consulted to make a final decision. The following data were collected from each study: name of the first author, year of publication, genotyping method, numbers of patients with RPL and healthy controls, genotypes and alleles frequencies in patients and controls for ACE I/D and PAI-1 4G/5G polymorphisms, minor allele frequency, and p-values for Hardy-Weinberg equilibrium (HWE) tests in control subjects. If a study included more than one case-control group, each studied group was considered as an independent dataset. For studies with overlapping data or samples by the same author, the larger sample size or the study that was published more recently was included in the meta-analysis.


Statistical Analysis

The strength of the association between ACE I/D and PAI-1 4G/5G polymorphisms and RPL risk in Iranian women was calculated using odds ratios (ORs) with 95% confidence intervals (CIs). The significance of the pooled OR was determined using the Z-test, in which a p-value <0.05 was considered significant. The pooled ORs for ACE I/D and PAI-1 4G/5G polymorphisms were estimated under all five genetic comparison models, i.e., allele (A vs B), homozygote (AA vs BB), heterozygote (BA vs BB), dominant (AA+BA vs BB), and recessive (AA vs BA+BB). A Cochrane-based Q statistical test was used to test between-studies heterogeneity, in which p-values <0.1 indicated the absence of indicated heterogeneity. Moreover, we used the inconsistency index (I2) (range of 0 to 100%) to quantify the proportion of the total variation due to heterogeneity, in which the heterogeneity was considered low, moderate, and high based on I2 values of 25%, 50%, and 75%, respectively. If heterogeneity was observed among the studies, the random-effects model (the DerSimonian and Laird method) was used to estimate the pooled OR. Otherwise, a fixed-effects model (the Mantel-Haenszel method) was adopted. For each study, the HWE in healthy subjects was estimated using the chi-square goodness-of-fit test and p<0.05 was considered statistically significant. Sensitivity analysis was performed by sequential omission of individual studies to assess the stability of pooled data in this meta-analysis. Moreover, sensitivity analysis was performed by excluding studies that deviated from the HWE. Both Begg’s funnel plot and Egger’s weighted regression tests were used to assess publication bias. If publication bias existed, the Duval and Tweedie non-parametric “trim and fill” method was applied to adjust results. All statistical analyses were performed using the Comprehensive Meta-analysis (CMA) software version 2.0 (Biostat, USA). Two-sided probability (p) values of <0.05 were considered statistically significant.


Results


Study Selection and Characteristics

A flow chart detailing the inclusion/exclusion process is shown in Figure 1. The primary online database queries and manual reference searches generated 337 potentially relevant studies that reported the association of ACE I/D and PAI-1 4G/5G polymorphisms with susceptibility to RPL. After the removal of duplicate articles, the search retrieved 218 items. Based on the title, abstract screening, or both, 129 articles were excluded according to the eligibility criteria. Subsequently, 75 publications were excluded because they were reviews, previous meta-analyses, and evaluated the association of RPL with other polymorphism of ACE and PAI-1 genes. Finally, a total of 14 studies involving eight studies with 783 patients and 761 controls on the ACE I/D polymorphism(6,18,29,32,33,34,35) and six studies with 1155 patients and 699 controls on the PAI-1 4G/5G polymorphism(18,31,34,3638) were included in this meta-analysis. One study in the present meta-analysis did not state the source of controls. Two genotyping methods were used, including ARMS-PCR and PCR-RFLP. The genotype distributions among the controls in the two studies were not consistent with the HWE on the ACE I/D polymorphism (Table 1).


Quantitative Data Synthesis


ACE I/D Polymorphism

The pooled results on the association of ACE I/D polymorphism with RPL risk in Iranian women are pre­sented in Table 2. When all eligible studies were pooled together, a significant association between ACE I/D polymorphism and increased risk of RPL in Iranian women was found only under three models i.e., allele [D vs I: OR=0.744, 95% CI: (0.640-0.864); p≤0.001, Figure 2A], dominant [DD+DI vs II: OR=0.774, 95% CI: (0.601-0.996); p=0.047, Figure 2B], and recessive [DD vs DI+II: OR=0.767, 95% CI: (0.611-0.963); p=0.022, Figure 2C]. When stratified by the number of recurrent miscarriages (RM), a significant association between the ACE I/D polymorphism and increased risk of RPL was detected in the group of studies with ≥2 RMs under the allele genetic model [D vs I: OR=0.666, 95% CI: (0.539-0.822); p≤0.001], but not in studies with ≥3 RM. Moreover, a significant association was found between ACE I/D and RPL in ARMS-PCR group studies under two genetic models i.e., allele [D vs I: OR=0.799, 95% CI: (0.659-0.967); p=0.022] and recessive [DD vs DI+II: OR=0.734, 95% CI: (0.544-0.989); p=0.042], and PCR-RFLP group studies under the allele model [D vs I: OR=0.667, 95% CI: (0.524-0.850); p=0.001).


PAI-1 4G/5G Polymorphism

Table 3 summarizes the main results of the meta-analysis for the PAI-1 4G/5G polymorphism and RPL in Iranian women. Overall pooled data showed that there was a significant association between the PAI-1 4G/5G polymorphism with RPL risk under all five genetic models i.e., allele [4G4G vs 5G5G: OR=2.352, 95% CI: (1.623-3.408); p≤0.001, Figure 3A], heterozygote [4G4G4 vs 5G5G5: OR=8.364, 95% CI: (4.744-14.756); p≤0.001, Figure 3B], homozygote [4G5G vs 5G5G: OR=2.192, 95% CI: (1.093-4.394); p=0.027, Figure 3B], dominant [4G4G4+4G5G vs 5G5G5: OR=2.354, 95% CI: (1.309-4.235); p=0.004, Figure 3D], and recessive [4G4G4 vs 4G5G+5G5G5: OR=5.208, 95% CI: (3.005-9.025); p≤0.001, Figure 3E]. When stratified by RM, a significant association between PAI-1 4G/5G polymorphism and increased risk of RPL was detected in the group of studies with ≥2 RMs under four genetic models i.e., allele [4G4G vs 5G5G: OR=2.083, 95% CI: (1.617-2.682); p≤0.001], homozygote [4G5G vs 5G5G: OR=8.390, 95% CI: (3.509-20.061); p≤0.001], dominant [4G4G4+4G5G vs 5G5G5: OR=2.003, 95% CI: (1.472-2.727); p≤0.001], and recessive [4G4G4 vs 4G5G+5G5G5: OR=5.871, 95% CI: (2.528-13.631); p≤0.001], and ≥3 under three genetic models i.e., allele [4G4G vs 5G5G: OR=2.653, 95% CI: (1.299-5.418); p=0.007], homozygote [4G5G vs 5G5G: OR=8.345, 95% CI: (3.955-17.606); p≤0.001], and recessive [4G4G4 vs 4G5G+5G5G5: OR=4.764, 95% CI: (2.305-9.845); p≤0.001].


Heterogeneity Test and Sensitivity Analysis

There was no between-study heterogeneity found in all five genetic models and thus the fixed-effect model was applied to calculate their combined OR. Moreover, we conducted a sensitivity analysis to investigate whether the absence of each study would alter the pooled ORs and stability of our results. However, we observed no significant change in the association level of ACE I/D and PAI-1 4G/5G polymorphisms with RPL risk in the Iranian population by excluding any of the studies. This suggests that that the current meta-analysis results were relatively robust and stable.


Publication Bias

The publication bias of the studies was assessed using a funnel plot and Egger’s test (Table 2 and Figure 4A,B). The funnel plot did not indicate any evidence of funnel plot asymmetry for the ACE I/D polymorphism. Moreover, the results of Egger’s test revealed no significant publication bias for the ACE I/D polymorphism. However, Begg’s funnel plot and Egger’s tests showed publication bias for the PAI-1 4G/5G polymorphism under two genetic models i.e., heterozygote (4G4G4 vs 5G5G5: PBeggs=0.060 and PEggers=0.021) and recessive (4G4G4 vs 4G5G+5G5G5: PBeggs=0.132 and PEggers=0.028). One probable explanation is that the results were underpowered and biased by limited sample sizes. Therefore, the Duval and Tweedie non-parametric “trim and fill” method was applied to adjust for publication bias on the PAI-1 4G/5G polymorphism under the heterozygote and recessive models. However, the results with and without “trim and fill” did not draw different results, indicating that the current meta-analysis results are statistically robust and reliable.


Discussion

The etiology of RPL is complicated, and several risk factors are involved in the development of the disease. In addition to fetal and maternal factors, including chromosomal abnormalities, endocrine and metabolic aberrations, and autoimmune abnormalities, genetic single nucleotide polymorphisms at different loci, also play essential roles in RPL(6,12,39). In this meta-analysis, we evaluated the association of the ACE I/D and PAI-1 4G/5G polymorphisms with RPL risk in Iranian women from all eligible case-control studies.

The 4G/5G polymorphism is a major genetic variant determinant of plasma PAI-1 levels. The 4G allele has been reported to increase the risk for different diseases such as atherosclerosis and coronary artery disease(40). On the other hand, the 5G allele may increase the risk of conditions such as abdominal aortic aneurysm. In this meta-analysis, our combined data based on six studies with 1,155 patients and 699 healthy subjects revealed that the PAI-1 4G/5G polymorphism was associated with an increased risk of RPL in Iranian women. In 2003, Wolf et al.(41) first reported an increased risk of RPL in Austrian women in association with the PAI-1 4G/5G polymorphism. However, later studies in different ethnicities yielded controversial results(18,34,42,43). In 2018, Adler et al.(44) evaluated the associations of the -675 I/D and 4G/5G polymorphisms and PAI-1 with susceptibility to pregnancy loss in European and worldwide populations. Their pooled data revealed that there was no significant relationship between the 4G/5G polymorphism and pregnancy loss both in Europe or elsewhere in the world. However, Huang et al.(12), in a meta-analysis based on 31 studies with 5617 patients and 3.952 healthy subjects reported that that the PAI-1 4G/5G polymorphism might contribute to the susceptibility of RPL; their subgroup analysis by ethnicity indicated a significantly elevated risk of RPL in Asians, Caucasians, and Africans. In 2015, Liu et al.(45), in a meta-analysis of 22 studies with 4306 patients and 3076 controls, showed that the PAI-1 4G/5G polymorphism might be associated with RPL in the overall population [OR=1.89; 95% CI: (1.34-2.67); p<0.001]. In a subgroup analysis, they found that the PAI-1 4G/5G polymorphism was significantly associated with an increased risk of RPL in Caucasian populations [OR=2.23; 95% CI: (1.44-3.46); p<0.001], but they reported that the PAI-1 4G/5G polymorphism was not significantly associated with RPL risk in Asian populations(45).

The current meta-analysis results showed that ACE I/D polymorphism was associated with increased risk of RPL in Iranian women under the allele genetic model [D vs I: OR=0.745, 95% CI: (0.641-0.866); p≤0.001]. Recently, Gumus(46) in a case-control study, showed that the ACE I/D polymorphism was associated with idiopathic recurrent pregnancy loss (IRPL), and women with DD or ID genotypes had a 72% higher risk of developing IRPL than women with the II genotype. In 2018, Aslebahar et al.(39), in a meta-analysis of 26 case-control studies with 3140 patients with RPL and 3.370 controls, showed that that ACE I/D polymorphism was associated with increased risk of RPL in the overall population. Similarly, Wang et al.(47), in a meta-analysis on 11 studies with a total of 3.357 individuals showed that the polymorphism was linked with an increased risk of recurrent miscarriage. By contrast, Pereza et al.(48), in a meta-analysis based on 1,192 patients and 736 healthy subjects, showed no association between the ACE I/D polymorphism and RPL. Moreover, they performed a case-control study on 149 women (with ≥3 spontaneous abortions) and 149 healthy subjects to evaluate the association among Croatian women. Similarly, they showed a negative association between the ACE I/D polymorphism and the risk of RPL(48). In 2013, Su et al.(49), in a meta-analysis based on 11 studies, reported a significant association between the ACE I/D polymorphism and IRPL. However, they found no significant association between the ACE I/D polymorphism and IRPL in Caucasian and non-Caucasian patients(49).

To our knowledge, this is the first meta-analysis to prove a significant association of the ACE I/D and PAI-1 4G/5G polymorphisms with RPL risk in Iranian women. However, the results presented here should be interpreted with caution because of several potential limitations. First, only published studies were included in this meta-analysis and some unpublished studies may have been missed, which may have biased the observed associations of ACE I/D and PAI-1 4G/5G polymorphisms with RPL in Iranian women. Second, there was relatively high heterogeneity under some genetic models. Third, the number of studies and the sample sizes were relatively small for analysis, thereby having insufficient power to estimate the association of ACE I/D and PAI-1 4G/5G polymorphisms with RPL in Iranian women. Fourth, the pooled estimates were based on unadjusted data, which might have affected the accuracy of the results. This is a meta-analysis with insufficient individual data to stratify results by other risk factors such as maternal age, environmental pollution, smoking; therefore, the association in these factors could not be assessed. Finally, RPL is a multifactorial disease influenced by many compound factors, including single or combined genetic polymorphisms and environmental factors. However, the impact of gene-gene, gene-environment interactions and also ACE I/D and PAI-1 4G/5G polymorphisms interactions were precluded owing to insufficient original data.


Conclusion

Considering all the results, the pooled data indicated that ACE I/D and PAI-1 4G/5G polymorphisms were associated with an increased risk of RPL in Iranian women. Moreover, these polymorphisms were associated with RPL risk by the number of previous miscarriages. These significant findings suggest that investigation might be adequate for ACE I/D and PAI-1 4G/5G polymorphisms in association with RPL in Iranian women.


Acknowledgement

I would like to express my sincere gratitude to Professor Mohammad Hasan Sheikhha for his motivation, knowledge and support during this research.

Ethics

Peer-review: Internally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: S.A.D., M.K.Z., R.S.T., A.J., M.N., S.R.M., H.N., Concept: R.B., Design: S.A.D., M.K.Z., R.S.T., A.J., M.N., S.R.M., H.N., Data Collection or Processing: S.A.D., H.N., Analysis or Interpretation: S.A.D., M.K.Z., R.S.T., A.J., M.N., S.R.M., H.N., Literature Search: S.A.D., M.K.Z., R.S.T., A.J., M.N., S.R.M., H.N., Writing: S.A.D., M.K.Z., R.S.T., A.J., M.N., S.R.M., H.N.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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