Prevalence of PAI-1 675 4G/5G and ACE I/D polymorphic variants in women with recurrent pregnancy losses

Keywords: recurrent miscarriage, inherited thrombophilia, genetic polymorphism

Abstract

Aim. The present study aimed to assess the distribution of inherited risk factors of thrombophilia among women with RPL. To determine the frequency and distribution of alleles and genotypes of polymorphic loci PAI-1 6754G/5G and ACE I/D among women with RPL. Methods. The study was carried out in a group of 97 women (57 controls and 40 women with RPL). Polymerase chain reaction and restriction fragment length polymorphism (RFLP) were used to identify the polymorphisms. Results. The frequency of 4G allele of PAI-1 675 5G/4G locus was more frequent in the group of women with RPL – 67 %, compared to 54 % in the control group. It was established that the presence of the 4G allele increases the risk of RPL by almost 2 times (Р = 0.01). In the group of women with RPL the frequency of carriers of DD genotype and D allele of ACE gene was higher than in the control group (31 % vs. 19 %), but no significant differences were found. The frequency of women with a combination of 4G4G and DD genotypes of the two studied loci was 16.6 % in the group with RPL versus 2.3 % in the control group. It was shown that the presence of homozygotes for two alleles 4G of the PAI-1 gene and D of the ACE gene leads to an 8-fold increased risk of RPL (OR = 8.6, CI: 0.9841-75.154, P = 0.04). Conclusions. Significance of PAI-1 675 4G/5G and ACE I/D polymorphic variants, especially in combination, in the predisposition to RPL was established.

References

Mc Namee K., Dawood F., Farquharson R. G. Thrombophilia and early pregnancy loss. Pract Res Clin Obstet Gynaecol. 2012. Vol. 26. P. 91–102. doi: 10.1016/j.bpobgyn.2011.10.002

Aslbahar F., Neamatzadeh H., Tabatabaiee R. S., Karimi-Zarchi M., Javaheri A., Mazaheri M., Foroughi E., Nasiri R. Associa-tion of Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism with Recurrent Pregnancy Loss: a Meta-Analysis of 26 Case-Control Studies. Rev Bras Ginecol Obstet. 2018. Vol. 40 (10). P. 631–641. doi: 10.1055/s-0038-1672137.

Adler G., Mahmutbegovic E., Valjevac A., Adler M. A., Mahmutbegovic N., Safranow K., Czerska E., Pawinska-Matecka A., Ciechanowicz I., Marjanovic D. Association Between - 675 ID, 4G/5G PAI-1 Gene Polymorphism and Pregnancy Loss : A Sys-tematic Review. Аcta Inform Med. 2018. Vol. 26 (3). P. 156–159. doi: 10.5455/aim.2018.26.156-159.

Garcia S., Sung N., Mullenix T. M., Dambaeva S., Beaman K., Gilman-Sachs A. Plasminogen activator inhibitor-1 4G/5G poly-morphism is associated with reproductive failure: metabolic, hormonal, and immune profiles. Am J Reprod Immunol. 2016. Vol. 76. P. 70–81. doi: 10.1111/aji.12516.

Krause M., Sonntag B., Klamroth R. Heinecke A., Scholz C., Langer C., Scharrer I., Greb R. R., Eckardstein A., Nowak-Gött U. Lipoprotein (a) and other prothrombotic risk factors in Caucasian women with unexplained recurrent miscarriage. Results of a multicentre case-control study. Thromb Haemost. 2005. Vol. 93 (5). P. 867–781. doi: 10.1160/TH04-08-0519

Kurzawińska G., Barlik M., Drews K., Agata Różycka A., Seremak-Mrozikiewicz A., Ożarowski M., Klejewski A., Czerny B., Wolski H. Coexistence of ACE (I/D) and PAI-1 (4G/5G) gene variants in recurrent miscarriage in Polish population. Ginekol Pol. 2016. Vol. 87 (4). P. 271–276. doi: 10.17772/gp/62203.

Hansda J., Roychowdhury J. Study of Thrombophilia in Recurrent Pregnancy Loss. J Obstet Gynaecol India. 2012. Vol. 62 (5). P. 536–540. doi: 10.1007/s13224-012-0197-x

Burzotta F., Iacoviello L., Di Castelnuovo A., Zamparelli R., D'Orazio A., Amore C., Schiavello R., Donati M. B., Maseri A., Possati G., Andreotti F. 4G/5G PAI-1 promoter polymorphism and acute – phase levels of PAI-1 following coronary by pass surgery: a prospective study. J. Thromb. Thrombolysis. 2003. Vol. 16. P. 149–154. doi: 10.1023/B:THRO.0000024052.79415.62

Buchholz Т., Lohse P., Rogenhofer N., Kosian E., Pihusch R., Thaler C. J. Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod. 2003. Vol. 18. 2473–2477. doi: 10.1093/humrep/deg474

Mello G., Parretti E., Gensini F., Sticchi E., Mecacci F., Scarselli G., Genuardi M., Abbate R., Fatini C. Maternal-fetal flow, negative events, and preeclampsia: role of ace i/d polymorphism. Hypertension. 2003. Vol. 41 (4). P. 932–937. doi: 10.1161/01.HYP.0000063146.40351.AD

Su M. T., Lin S. H., Chen Y. C., Kuo P. L. Genetic association studies of ace and pai-1 genes in women with recurrent preg-nancy loss: a systematic review and meta-analysis. Thrombosis and Haemostasis. 2013. Vol. 109 (1). P. 8–15. doi: 10.1160/TH12-08-0584

Correa-Noronha S. A., Noronha S.M., Alecrim C., Mesquita Ade C., Brito G. S., Junqueira M. G., Leite D. B., Carvalho C. V., Silva I. D. Association of angiotensin-converting enzyme i gene i/d polymorphism with endometrial but not with ovarian cancer. Gynecological Endocrinology. 2012. Vol. 28 (11). P. 889–891. doi: 10.3109/09513590.2012.683060

Ahmed H. K., Elgoraish A. G., Abdalla S.E., Babker M. A., Alfeel A. H, Abbas A. O., Mohamedahmed K. A., Elzaki S. G. Meta-analysis – fibrinolysis – coagulation – ACE – PAI-1 – recurrent pregnancy loss. Association of Plasminogen Activator Inhibitor-1 4G/5G and Angiotensin-Converting Enzyme I/D Polymorphisms with Recurrent Pregnancy Loss in Sudanese Women: A Case-Control study. International Journal of Biomedicine. 2023 Vol. 13 (1). P. 127–133. doi: 10.21103/Article13(1)_OA18

Nina Pereza N., Ostojić S., Zdravčević M., Volk M., Kapović M., Peterlin B. Insertion/deletion polymorphism in intron 16 of ACE gene in idiopathic recurrent spontaneous abortion: case-control study, systematic review and meta-analysis Reprod Biomed Online. 2016. Vol. 32 (2). P. 237–246. doi: 10.1016/j.rbmo.2015.11.003.