11 April 2015: Meta-Analysis
Meta-Analysis of the Association between Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Recurrent Pregnancy Loss
Xuejiao Li BCDEF , Yukun Liu BCD , Rui Zhang CD , Jianping Tan CD , Libin Chen F , Yinglin Liu ABCDEF
DOI: 10.12659/MSM.892898
Med Sci Monit 2015; 21:1051-1056
Abstract
BACKGROUND: The association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and recurrent pregnancy loss (RPL) risk is still contradictory. We thus performed a meta-analysis.
MATERIAL AND METHODS: Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. An odds ratio (OR) with a 95% confidence interval (CI) was used to assess the association between PAI-1 4G/5G polymorphism and RPL risk.
RESULTS: A total of 22 studies with 4306 cases and 3076 controls were included in this meta-analysis. We found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34–2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44–3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84–2.59; P=0.18).
CONCLUSIONS: In conclusion, this meta-analysis suggests that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians.
Keywords: Abortion, Habitual - genetics, Genetic Association Studies, Genetic Predisposition to Disease, Plasminogen Activator Inhibitor 1 - genetics, Polymorphism, Single Nucleotide - genetics, Pregnancy, Publication Bias, Risk Factors
Background
Recurrent pregnancy loss (RPL) is a common clinical problem that may occur during pregnancy. About 15% of clinically recognized pregnancies could suffer from RPL before the 20th week of gestation, with no known cause [1]. The pathogenesis of RPL remains unknown in many patients, and approximately 55% of patients are suspected to have thrombophilic defects [2].
Thrombophilia is a common cause of RPL and is found in 40–50% of cases [3]. Laude et al. found that levels of circulating procoagulant microparticles were higher in women with RPL when compared with controls [4]. Thrombophilia might cause a syncytiotrophoblast invasion of the maternal blood vessels, which could lead to the formation of microthrombosis at the site of implantation and result in RPL and implantation failure [5].
Plasminogen activator inhibitor-1 (PAI-1) is the urinary plasminogen activator and principal inhibitor of tissue. The main function of PAI-1 is converting plasminogen to the proteolytic enzyme plasmin [6]. Sun and colleagues found that PAI-1 4G/5G polymorphism was significant positive explanatory variable for polycystic ovary syndrome (PCOS) patients with spontaneous abortions [7]. In addition, PAI-1 4G/5G polymorphism was associated with increased PAI-1 concentrations and hypofibrinolysis and contributed to early pregnancy loss [7]. Many studies assessed the association between PAI-1 4G/5G polymorphism and RPL risk [8–29]. However, the result was still uncertain. A meta-analysis found that PAI-1 4G/5G polymorphism did not increase the risk of RPL. However, recent studies did not confirm this result [24,25,27]. Therefore, we conducted this meta-analysis to investigate the association between PAI-1 4G/5G polymorphism and RPL risk.
Material and Methods
PUBLICATION SEARCH:
Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. The following terms and strategies were used for the search: (“Plasminogen activator inhibitor-1” OR “PAI-1”) AND (“single nucleotide polymorphism” OR “SNP” OR “genetic variation” OR “genetic polymorphism”) AND (“Recurrent pregnancy loss” OR “RPL”). To avoid possible missing of qualified trails, introduction and reference list of eligible trails identified through primary search were screened manually. No language restriction was applied when searching.
INCLUSION AND EXCLUSION CRITERIA:
The following criteria were used to screen eligible studies for this meta-analysis: (1) a case
DATA EXTRACTION:
Two authors extracted the data independently. These data included: the first author, year, ethnicity, genotype distribution, and sample size. Disagreement in data extraction was resolved by group discussion by referring to original studies with a third reviewer.
STATISTICAL ANALYSIS:
The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the association between PAI-1 4G/5G polymorphism and RPL risk. The recessive genetic model (4G/4G
Results
STUDY CHARACTERISTICS:
After searching and screening with preset criteria, a total of 22 studies with 4306 cases and 3076 controls were included for this meta-analysis. Four studies were conducted in Asians and 18 in Caucasians. The characteristics and the HWE results of the included studies are listed in Table 1. Four studies were not in HWE.
META-ANALYSIS RESULTS:
As shown in Figure 1, we found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34–2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44–3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84–2.59; P=0.18). Results of the meta-analysis are listed in Table 2. In the sensitivity analysis, when the fixed-effects model was used, the result was still positive (OR=1.87; 95% CI 1.64–2.13; P<0.00001). When the studies without HWE were excluded, the result was not changed (OR=1.56; 95% CI 1.12–2.19; P=0.009). Furthermore, when the studies with small sample size were excluded, the result was also not changed (OR=1.98; 95% CI 1.25–3.13; P=0.004). The results of sensitivity analysis are listed in Table 3.
Results from the cumulative meta-analysis suggest that the evidence was consistent over time (Figure 2), indicating that the results of this meta-analysis are robust. Significant heterogeneity (I2=81%) was detected in the recessive genetic model. Thus, we used the Galbraith plot to explore the source of the heterogeneity. As shown in Figure 3, 10 studies were considered as outliers. When these studies were excluded, the heterogeneity was decreased. No obvious heterogeneity among the remaining studies could be found (I2=0%). Furthermore, the result was significant (OR=1.48, 95% CI 1.22–1.79, P<0.0001). No significant publication bias was found by Begg’s funnel plot (Figure 4) and Egger’s test (P=0.313).
Discussion
Our previous meta-analysis investigated the association between PAI-1 4G/5G polymorphism and RPL risk [30]. However, that meta-analysis did not find a positive association between PAI-1 4G/5G polymorphism and risk of RPL. Several new studies have been published since then. Thus, we did a new meta-analysis. When these new studies were included, we found that PAI-1 4G/5G polymorphism was significantly associated with risk of RPL, indicating that PAI-1 4G/5G polymorphism carriers might have increased RPL risk. In the subgroup analysis based on race, PAI-1 4G/5G polymorphism showed increased RPL risk in Caucasians. However, no positive association was found in Asians. Ethnic differences can occur in genotype frequencies, which might account for the different results. In addition, there were only four studies with Asians. More studies with Asian populations are needed to validate this result. We then did cumulative meta-analysis. We found that the result from our meta-analysis was stable. In the sensitivity analyses, we also found the results were not altered, indicating this meta-analysis was robust.
In human and animal models, PAI-1 was involved not only in fibrinolysis regulation, but also in extracellular proteolytic processes during ovulation, ovarian follicle growth, and embryo implantation [31,32]. Much evidence has suggested that abnormal levels of PAI-1 significantly increase miscarriage and complicated pregnancy rates [33]. Additionally, Glueck et al. suggested that PAI activity was a significant positive explanatory variable for the number of miscarriages [34]. Furthermore, Glueck et al. found that administration of metformin throughout pregnancy in women with PCOS reduced the risk of first-trimester spontaneous abortion [35]. Palomba and coworkers also confirmed that metformin reduced PAI-1 activity in women with PCOS and abortion risk [36]. Therefore, it might be possible that increased PAI-1 associated with high RPL risk and PAI-1 4G/5G polymorphism might influence RPL risk.
There were some limitations in this meta-analysis. First, lack of the original data limited the evaluation of gene-gene and gene-environment interactions. Second, Dawson et al. indicated that PAI-1 level was not only changed by PAI- 1 4G/5G polymorphism, but also by concentration of blood sugar, insulin, and triglycerides [37]. However, we did not adjust these factors in this meta-analysis due to lack of original data. Third, the studies included in our meta-analysis were small. Thus our meta-analysis had little statistical power to assess the association between the PAI-1 4G/5G polymorphism and RPL risk.
Conclusions
The results of this meta-analysis suggest that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians. Large-scale studies are necessary to validate this result.
References
1. Cohn DM, Goddijn M, Middeldorp S, Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy: J Thromb Haemost, 2010; 8(10); 2208-13, pmid: 20704646
2. Middeldorp S, Pregnancy failure and heritable thrombophilia: Semin Hematol, 2007; 44(2); 93-97, pmid: 17433901
3. Brenner B, Sarig G, Weiner Z, Thrombophilic polymorphisms are common in women with fetal loss without apparent cause: Thromb Haemost, 1999; 82(1); 6-9, pmid: 10456445
4. Laude I, Rongières-Bertrand C, Boyer-Neumann C, Circulating procoagulant microparticles in women with unexplained pregnancy loss: a new insight: Thromb Haemost, 2001; 85(1); 18-21, pmid: 11204573
5. Azem F, Many A, Ben Ami I, Increased rates of thrombophilia in women with repeated IVF failures: Hum Reprod, 2004; 19(2); 368-70, pmid: 14747183
6. Dellas C, Loskutoff DJ, Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease: Thromb Haemost, 2005; 93(4); 631-40, pmid: 15841306
7. Sun L, Lv H, Wei W, Angiotensin-converting enzyme D/I and plasminogen activator inhibitor-1 4G/5G gene polymorphisms are associated with increased risk of spontaneous abortions in polycystic ovarian syndrome: J Endocrinol Invest, 2010; 33(2); 77-82, pmid: 19636212
8. Wolf CE, Haubelt H, Pauer HU, Recurrent pregnancy loss and its relation to FV Leiden, FII G20210A and polymorphisms of plasminogen activator and plasminogen activator inhibitor: Pathophysiol Haemost Thromb, 2003; 33; 134-37, pmid: 15170393
9. Buchholz T, Lohse P, Rogenhofer N, Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages: Hum Reprod, 2003; 18; 2473-77, pmid: 14585904
10. Dossenbach-Glaninger A, van Trotsenburg M, Dossenbach M, Plasminogen activator inhibitor 1 4G/5G polymorphism and coagulation factor XIII Val34Leu polymorphism: impaired fibrinolysis and early pregnancy loss: Clin Chem, 2003; 49; 1081-86, pmid: 12816904
11. Guan LX, Du XY, Wang JX, Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5,10-methylenetetrahydrofolate reductase gene with recurrent early spontaneous abortion: Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2005; 22(3); 330-33, pmid: 15952129
12. Coulam CB, Jeyendran RS, Fishel LA, Roussev R, Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage: Am J Reprod Immunol, 2006; 55(5); 360-68, pmid: 16635210
13. Coulam CB, Wallis D, Weinstein J, Comparison of thrombophilic gene mutations among patients experiencing recurrent miscarriage and deep vein thrombosis: Am J Reprod Immunol, 2008; 60(5); 426-31, pmid: 18803625
14. Goodman C, Hur J, Goodman CS, Are polymorphisms in the ACE and PAI-1 genes associated with recurrent spontaneous miscarriages?: Am J Reprod Immunol, 2009; 62; 365-70, pmid: 19821806
15. Al Sallout RJ, Sharif FA, Polymorphisms in NOS3, ACE and PAI-1 genes and risk of spontaneous recurrent miscarriage in the Gaza Strip: Med Princ Pract, 2010; 19; 99-104, pmid: 20134171
16. Ivanov P, Komsa-Penkova R, Ivanov I, Plasminogen activator inhibitor type 1 activity in women with unexplained very early recurrent pregnancy loss: Akush Ginekol (Sofiia), 2010; 49(5); 3-8, pmid: 21268395
17. Ivanov P, Komsa-Penkova R, Konova E, Combined thrombophilic factors among women with late recurrent spontaneous abortions: Akush Ginekol (Sofiia), 2011; 50(3); 8-12, pmid: 21916309
18. Aarabi M, Memariani T, Arefi S, Polymorphisms of plasminogen activator inhibitor- 1, angiotensin converting enzyme and coagulation factor XIII genes in patients with recurrent spontaneous abortion: J Matern Fetal Neonatal Med, 2011; 24; 545-48, pmid: 20822334
19. Jeddi-Tehrani M, Torabi R, Zarnani AH, Analysis of plasminogen activator inhibitor-1, integrin beta3, beta fibrinogen, and methylenetetrahydrofolate reductase polymorphisms in Iranian women with recurrent pregnancy loss: Am J Reprod Immunol, 2011; 66; 149-56, pmid: 21241403
20. Idali F, Zareii S, Mohammad-Zadeh A, Plasminogen activator inhibitor 1 and methylenetetrahydrofolate reductase gene mutations in iranian women with polycystic ovary syndrome: Am J Reprod Immunol, 2012; 68(5); 400-7, pmid: 22882325
21. Torabi R, Zarei S, Zeraati H, Combination of thrombophilic gene polymorphisms as a cause of increased the risk of recurrent pregnancy loss: J Reprod Infertil, 2012; 13(2); 89-94, pmid: 23926530
22. Ozdemir O, Yenicesu GI, Silan F, Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations: Genet Test Mol Biomarkers, 2012; 16; 279-86, pmid: 22047507
23. Parveen F, Tuteja M, Agrawal S, Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women: Arch Gynecol Obstet, 2013; 288(5); 1171-77, pmid: 23685927
24. Magdoud K, Herbepin VG, Touraine R, Plasminogen activator inhibitor 1 4G/5G and -844G/A variants in idiopathic recurrent pregnancy loss: Am J Reprod Immunol, 2013; 70; 246-52, pmid: 23521508
25. Subrt I, Ulcova-Gallova Z, Cerna M, Recurrent pregnancy loss, plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and antiphospholipid antibodies in Czech women: Am J Reprod Immunol, 2013; 70; 54-58, pmid: 23445116
26. Jeon YJ, Kim YR, Lee BE, Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women: Thromb Haemost, 2013; 110; 742-50, pmid: 23903286
27. Khosravi F, Zarei S, Ahmadvand N, Association between plasminogen activator inhibitor 1 gene mutation and different subgroups of recurrent miscarriage and implantation failure: J Assist Reprod Genet, 2014; 31; 121-24, pmid: 24189965
28. Kim JJ, Choi YM, Lee SK, The PAI-1 4G/5G and ACE I/D Polymorphisms and Risk of Recurrent Pregnancy Loss: A Case-Control Study: Am J Reprod Immunol, 2014; 72(6); 571-76, pmid: 25078885
29. Lino FL, Traina E, Barreto JA, Thrombophilic Mutations and Polymorphisms, Alone or in Combination, and Recurrent Spontaneous Abortion: Clin Appl Thromb Hemost, 2014 [Epub ahead of print]
30. Su MT, Lin SH, Chen YC, Kuo PL, Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss: a systematic review and meta-analysis: Thromb Haemost, 2013; 109(1); 8-15, pmid: 23179239
31. Piquette GN, Simón C, el Danasouri I, Gene regulation of interleukin-1 beta, interleukin-1 receptor type I, and plasminogen activator inhibitor-1 and -2 in human granulosa-luteal cells: Fertil Steril, 1994; 62(4); 760-70, pmid: 7926084
32. Wang Y, Long J, Wang X, Sun Y, Association of the plasminogen activator inhibitor-1 (PAI-1) Gene -675 4G/5G and -844 A/G promoter polymorphism with risk of keloid in a Chinese Han population: Med Sci Monit, 2014; 20; 2069-73, pmid: 25350781
33. Kujovich JL, Thrombophilia and pregnancy complications: Am J Obstet Gynecol, 2004; 191(2); 412-24, pmid: 15343215
34. Glueck CJ, Wang P, Fontaine RN, Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome: Metabolism, 1999; 48(12); 1589-95, pmid: 10599993
35. Glueck CJ, Phillips H, Cameron D, Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study: Fertil Steril, 2001; 75(1); 46-52, pmid: 11163815
36. Palomba S, Orio F, Falbo A, Plasminogen activator inhibitor 1 and miscarriage after metformin treatment and laparoscopic ovarian drilling in patients with polycystic ovary syndrome: Fertil Steril, 2005; 84(3); 761-65, pmid: 16169420
37. Dawson S, Hamsten A, Wiman B, Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity: Arterioscler Thromb, 1991; 11(1); 183-90, pmid: 1670989
In Press
Clinical Research
Institutional and Regional Variations in Access to Clinical Trials and Next-Generation Sequencing in Turkis...Med Sci Monit In Press; DOI: 10.12659/MSM.951027
Clinical Research
Low-Intensity Blood Flow-Restricted Multi-Joint Exercise Improves Muscle Function in Patients With Patellof...Med Sci Monit In Press; DOI: 10.12659/MSM.950516
Review article
Musculoskeletal Ultrasound and MRI in the Evaluation of Chemotherapy-Induced Peripheral Neuropathy: A ReviewMed Sci Monit In Press; DOI: 10.12659/MSM.951283
Clinical Research
Sensory Processing, Dissociation, and Affective Symptoms in Misophonia: A Cross-Sectional Study of 35 AdultsMed Sci Monit In Press; DOI: 10.12659/MSM.950938
Most Viewed Current Articles
17 Jan 2024 : Review article 10,187,196
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
13 Nov 2021 : Clinical Research 3,708,487
Acceptance of COVID-19 Vaccination and Its Associated Factors Among Cancer Patients Attending the Oncology ...DOI :10.12659/MSM.932788
Med Sci Monit 2021; 27:e932788
14 Dec 2022 : Clinical Research 2,341,643
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
16 May 2023 : Clinical Research 706,524
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387