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Journal of Assisted Reproduction and Genetics
Published in: Journal of Assisted Reproduction and Genetics 4/2019

01-04-2019 | Miscarriage | Genetics

The interaction effect of angiogenesis and endothelial dysfunction-related gene variants increases the susceptibility of recurrent pregnancy loss

Authors: E. A. Trifonova, M. G. Swarovskaya, O. A. Ganzha, O. V. Voronkova, T. V. Gabidulina, V. A. Stepanov

Published in: Journal of Assisted Reproduction and Genetics | Issue 4/2019

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Abstract

Purpose

The role of genetic polymorphisms in the pathogenesis of recurrent pregnancy loss (RPL) has been studied intensively. Complex diseases, including miscarriage, are believed to have a polygenic basis, and gene–gene interactions can play a significant role in the etiology of the disease. This study was conducted to investigate the association of gene–gene interactions with angiogenesis, endothelial dysfunction-related gene polymorphisms, and RPL.

Methods

A case–control study was conducted with 253 unrelated RPL patients with 2 or more spontaneous pregnancy losses and 339 healthy women with no history of pregnancy complications. Genotyping of single-nucleotide polymorphisms (SNPs) was performed using real-time polymerase chain reaction (real-time PCR), restriction fragment length polymorphism (RFLP), or allele-specific polymerase chain reaction methods.

Results

The genotypes 677TT of the MTHFR gene, 936TT, 936CT, and 634CC, 634GC of the VEGF gene, and allele 894T of the NOS3 gene were associated with a predisposition to RPL in the Russian population. A significant role of additive and epistatic effects in the gene–gene interactions of the SNPs of SERPINE-1, ACE, NOS3, MTHFR, and VEGF genes in RPL was demonstrated.

Conclusions

The results showed that gene–gene interactions are important for RPL susceptibility. Additionally, analysis of the genotype combinations of several allelic variants provides more information on RPL risk than analysis of independent polymorphic markers.
Literature
1.
2.
Rull K, Nagirnaja L, Laan M. Genetics of recurrent miscarriage: challenges, current knowledge, future directions. Front Genet. 2012;3(34):1–13.
3.
Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet. 2015;291(3):671–9.PubMedCrossRef
4.
Kolte AM, Nielsen HS, Steffensen R, et al. Inheritance of the 8.1 ancestral haplotype in recurrent pregnancy loss. Evol Med Public Health. 2015;2015(1):325–31.PubMedPubMedCentral
5.
Shi X, Xie X, Jia Y, Li S. Maternal genetic polymorphisms and unexplained recurrent miscarriage: a systematic review and meta-analysis. Clin Genet. 2017;91(2):265–84.PubMedCrossRef
6.
Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury MJ. A navigator for human genome epidemiology. Nat Genet. 2008;40(2):124–5.PubMedCrossRef
7.
Arias-Sosa LA, Acosta ID, Lucena-Quevedo E, Moreno-Ortiz H, Esteban-Pérez C, Forero-Castro M. Genetic and epigenetic variations associated with idiopathic recurrent pregnancy loss. J Assist Reprod Genet. 2018;35(3):355–66.PubMedPubMedCentralCrossRef
8.
Pereza N, Ostojić S, Kapović M, Peterlin B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril. 2017;107(1):150–9.PubMedCrossRef
9.
10.
Tang W, Zhou X, Chan Y, Wu X, Luo Y. p53 codon 72 polymorphism and recurrent pregnancy loss: a meta-analysis. J Assist Reprod Genet. 2011;28(10):965–9.PubMedPubMedCentralCrossRef
11.
Chen H, Yang X, Wang Z. Association between p53 Arg72Pro polymorphism and recurrent pregnancy loss: an updated systematic review and meta-analysis. Reprod BioMed Online. 2015;31(2):149–53.PubMedCrossRef
12.
Li X, Liu Y, Zhang R, Tan J, Chen L, Liu Y. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Med Sci Monit. 2015;21:1051–6.PubMedPubMedCentralCrossRef
13.
Zhang B, Dai B, Zhang X, Wang Z. Vascular endothelial growth factor and recurrent spontaneous abortion: a meta-analysis. Gene. 2012;507(1):1–8.PubMedCrossRef
14.
Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene. 2013;514:105–11.PubMedCrossRef
15.
Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016;293(2):283–90.PubMedCrossRef
16.
Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril. 2006;86(6):1716–22.PubMedCrossRef
17.
Pereza N, Peterlin B, Volk M, Kapović M, Ostojić S. A critical update on endothelial nitric oxide synthase gene variations in women with idiopathic recurrent spontaneous abortion: genetic association study, systematic review and meta-analyses. Mol Hum Reprod. 2015;21(5):466–78.PubMedCrossRef
18.
Su MT, Lin SH, Chen YC. Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod Update. 2011;17(6):803–12.PubMedCrossRef
19.
Cao Y, Zhang Z, Xu J, Wang J, Yuan W, Shen Y, et al. Genetic association studies of endothelial nitric oxide synthase gene polymorphisms in women with unexplained recurrent pregnancy loss: a systematic and meta-analysis. Mol Biol Rep. 2014;41(6):3981–9.PubMedCrossRef
20.
Yang C, Fangfang W, Jie L, Yanlong Y, Jie W, Xuefei L, et al. Angiotensin-converting enzyme insertion/deletion (I/D) polymorphisms and recurrent pregnancy loss: a meta-analysis. J Assist Reprod Genet. 2012;29(1):1167–73.PubMedPubMedCentralCrossRef
21.
22.
Su MT, Lin SH, Chen YC, Kuo PL. Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss. Thromb Haemost. 2013;109(1):8–15.PubMedCrossRef
23.
Chen H, Nie S, Lu M. Association between plasminogen activator Inhibitor-1 gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis. Am J Reprod Immunol. 2015;73(4):292–300.PubMedCrossRef
24.
Wang Z, Wang P, Wang X. Significant association between angiotensin-converting enzyme gene insertion/deletion polymorphism and risk of recurrent miscarriage: a systematic review and meta-analysis. Metabolism. 2013;62(9):1227–38.PubMedCrossRef
25.
Aschard H, Lutz S, Maus B, Duell EJ, Fingerlin TE, Chatterjee N, et al. Challenges and opportunities in genome-wide environmental interaction (GWEI) studies. Hum Genet. 2012;131(10):1591–613.PubMedPubMedCentralCrossRef
26.
27.
28.
Nasr HB, Dimassi S, M’hadhbi R, Debbabi H, Kortas M, Tabka Z, et al. Functional G894T (rs1799983) polymorphism and intron-4 VNTR variant of nitric oxide synthase (NOS3) gene are susceptibility biomarkers of obesity among Tunisians. Obes Res Clin Pract. 2016;10(4):465–75.PubMedCrossRef
29.
Blasiak J, Smolarz B. Plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G promoter polymorphism is not associated with breast cancer. Acta Biochim Pol. 2000;47(1):191–9.PubMed
30.
Kalita J, Somarajan BI, Kumar B, Mittal B, Misra UK. A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke. Clin Chim Acta. 2011;412(7–8):642–6.PubMedCrossRef
31.
El-Aziz TAA, Mohamed RH. Influence of MTHFR C677T gene polymorphism in the development of cardiovascular disease in Egyptian patients with rheumatoid arthritis. Gene. 2017;610:127–32.CrossRef
32.
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–5.PubMedCrossRef
33.
34.
Chung Y, Lee SY, Elston RC, Park T. Odds ratio based multifactor-dimensionality reduction method for detecting gene–gene interactions. Bioinformatics. 2007;23(1):71–6.PubMedCrossRef
35.
Yousefian E, Kardi MT, Allahveisi A. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism in Iranian women with idiopathic recurrent pregnancy losses. Iranian Red Crescent Med J. 2014;16(7):1–4.CrossRef
36.
Isaoglu U, Ulug P, Delibas IB, et al. The association between inherited thrombophilia and recurrent pregnancy loss in Turkish women. Clin Exp Obstet Gynecol. 2014;41(2):177–81.PubMedCrossRef
37.
Bozikova A, Gabrikova D, Pitonak J, Bernasovska J, Macekova S, Lohajova-Behulova R. Ethnic differences in the association of thrombophilic polymorphisms with obstetric complications in Slovak and Roma (Gypsy) populations. Genet Test Mol Biomarkers. 2015;19(2):98–102.PubMedPubMedCentralCrossRef
38.
Parveen F, Faridi RM, Alam S, Agrawal S. Genetic analysis of eNOS gene polymorphisms in association with recurrent miscarriage among North Indian women. Reprod BioMed Online. 2011;23(1):124–31.PubMedCrossRef
39.
40.
Najafi T, Novin MG, Ghazi R, Khorram O. Altered endometrial expression of endothelial nitric oxide synthase in women with unexplained recurrent miscarriage and infertility. Reprod BioMed Online. 2012;25(4):408–14.PubMedPubMedCentralCrossRef
41.
Luo L, Li DH, Wei SG, Zhang HB, Li SB, Zhao J. Polymorphisms in the endothelial nitric oxide synthase gene associated with recurrent miscarriage. Genet Mol Res. 2013;12(3):3879–86.PubMedCrossRef
42.
Shin SJ, Lee HH, Cha SH, Kim JH, Shim SH, Choi DH, et al. Endothelial nitric oxide synthase gene polymorphisms (− 786T> C, 4a4b, 894G> T) and haplotypes in Korean patients with recurrent spontaneous abortion. Eur J Obstet Gynecol Reprod Biol. 2010;152(1):64–7.PubMedCrossRef
43.
Zammiti W, Mtiraoui N, Mahjoub T. Lack of consistent association between endothelial nitric oxide synthase gene polymorphisms, homocysteine levels and recurrent pregnancy loss in Tunisian women. Am J Reprod Immunol. 2008;59(2):139–45.PubMedCrossRef
44.
Lee HH, Hong SH, Shin SJ, Ko JJ, Oh D, Kim NK. Association study of vascular endothelial growth factor polymorphisms with the risk of recurrent spontaneous abortion. Fertil Steril. 2010;93(4):1244–7.PubMedCrossRef
45.
Traina E, Daher S, Moron AF, Sun SY, Franchim CS, Mattar R. Polymorphisms in VEGF, progesterone receptor and IL-1 receptor genes in women with recurrent spontaneous abortion. J Reprod Immunol. 2011;88(1):53–7.PubMedCrossRef
46.
Papazoglou D, Galazios G, Papatheodorou K, Liberis V, Papanas N, Maltezos E, et al. Vascular endothelial growth factor gene polymorphisms and idiopathic recurrent pregnancy loss. Fertil Steril. 2005;83(4):959–63.PubMedCrossRef
47.
Lash GE, Cartwright JE, Whitley GS. The effects of angiogenic growth factors on extravillous trophoblast invasion and motility. Placenta. 1999;20:661–7.PubMedCrossRef
48.
Yalcintepe SA, Silan F, Hacivelioglu SO, et al. Fetal VEGF genotype is more important for abortion risk than mother genotype. Int J Mol Cell Med. 2014;3(2):88–94.PubMedPubMedCentral
49.
Amirchaghmaghi E, Rezaei A, Moini A, et al. Gene expression analysis of VEGF and its receptors and assessment of its serum level in unexplained recurrent spontaneous abortion. Cell J. 2015;4(16):538–45.
50.
Galazios G, Papazoglou D, Tsikouras P, Kolios G. Vascular endothelial growth factor gene polymorphisms and pregnancy. J Matern Fetal Neonatal Med. 2009;22(5):371–8.PubMedCrossRef
51.
Andraweera PH, Dekker GA, Roberts CT. The vascular endothelial growth factor family in adverse pregnancy outcomes. Hum Reprod Update. 2012;18(4):436–57.PubMedCrossRef
52.
Sun L, Lv H, Wei W, Zhang D, Guan Y. 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 Investig. 2010;33(2):77–82.CrossRef
53.
Labied S, Blacher S, Carmeliet P, Noël A, Frankenne F, Foidart JM, et al. Transient reduction of placental angiogenesis in PAI-1-deficient mice. Physiol Genomics. 2011;43(4):188–98.PubMedCrossRef
54.
Subrt I, Ulcova-Gallova Z, Cerna M, Hejnalova M, Slovanova J, Bibkova K, et al. Recurrent pregnancy loss, plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and antiphospholipid antibodies in Czech women. Am J Reprod Immunol. 2013;70(1):54–8.PubMedCrossRef
55.
Kim JJ, Choi YM, Lee SK, Yang KM, Paik EC, Jeong HJ, et al. 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):571–6.PubMedCrossRef
56.
57.
Kim DK, Kim JW, Kim S, Gwon HC, Ryu JC, Huh JE, et al. Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol. 1997;17:3242–7.PubMedCrossRef
58.
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(2):99–104.PubMedCrossRef
59.
Floridon C, Nielsen O, Hølund B, Sweep F, Sunde L, Thomsen SG, et al. Does plasminogen activator inhibitor-1 (PAI-1) control trophoblast invasion? A study of fetal and maternal tissue in intrauterine, tubal and molar pregnancies. Placenta. 2000;21(8):754–62.PubMedCrossRef
60.
Dossenbach-Glaninger A, van Trotsenburg M, Schneider B, Oberkanins C, Hopmeier P. ACE I/D polymorphism and recurrent first trimester pregnancy loss: interaction with SERPINE1 4G/5G and F13 Val34Leu polymorphisms. Br J Haematol. 2008;141(2):269–71.PubMedCrossRef
61.
Buchholz T, Lohse P, Rogenhofer N, et al. Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod. 2003;18(11):2473–7.PubMedCrossRef
Metadata
Title
The interaction effect of angiogenesis and endothelial dysfunction-related gene variants increases the susceptibility of recurrent pregnancy loss
Authors
E. A. Trifonova
M. G. Swarovskaya
O. A. Ganzha
O. V. Voronkova
T. V. Gabidulina
V. A. Stepanov
Publication date
01-04-2019
Publisher
Springer US
Keyword
Miscarriage
Published in
Journal of Assisted Reproduction and Genetics / Issue 4/2019
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-019-01403-2

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