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The MDM2 promoter T309G polymorphism was associated with preeclampsia susceptibility

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Preeclampsia (PE) is a hypertensive disorder of pregnancy in which abnormal proliferation and apoptosis of placenta trophoblast has a pivotal role in its pathophysiology. The aim of the current study was to examine the association between Mouse Double Minute 2 (MDM2) T309G and 40 bp insertion/deletion (I/D) polymorphisms and PE risk.

Methods

A case-control study was conducted on 208 PE women and 164 healthy pregnant women matching age, sex, and ethnicity. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR methods were used for genotyping.

Results

The MDM2 309GG genotype was associated with PE, and this genotype was found to be a risk factor for PE. There was no association between the MDM2 I/D polymorphism and PE. The haplotype-based association analysis revealed no association between MDM2 T309G and 40 bp I/D polymorphisms and PE. The frequency of TT-DD and GG-DD combined genotypes were significantly higher in PE women with marginal P values (P = 0.046).

Conclusions

The MDM2 309GG genotype was associated with higher risk of PE. The TT-DD and GG-DD combined genotypes were higher in PE women.

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References

  1. Bulletins--Obstetrics ACoP. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99(1):159–167.

  2. Zhang J, Zeisler J, Hatch MC, Berkowitz G. Epidemiology of pregnancy-induced hypertension. Epidemiol Rev. 1997;19(2):218–32.

    Article  CAS  PubMed  Google Scholar 

  3. Carty DM, Delles C, Dominiczak AF. Preeclampsia and future maternal health. J Hypertens. 2010;28(7):1349–55. doi:10.1097/HJH.0b013e32833a39d0.

    Article  CAS  PubMed  Google Scholar 

  4. Dekker G, Sukcharoen N. Etiology of preeclampsia: an update. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2004;87(Suppl 3):S96–103.

    PubMed  Google Scholar 

  5. Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med. 2001;344(12):867–72. doi:10.1056/NEJM200103223441201.

    Article  CAS  PubMed  Google Scholar 

  6. Mendilcioglu I, Karaveli S, Erdogan G, Simsek M, Taskin O, Ozekinci M. Apoptosis and expression of Bcl-2, Bax, p53, caspase-3, and Fas, Fas ligand in placentas complicated by preeclampsia. Clinical and experimental obstetrics & gynecology. 2011;38(1):38–42.

    CAS  Google Scholar 

  7. Whitley GS, Dash PR, Ayling LJ, Prefumo F, Thilaganathan B, Cartwright JE. Increased apoptosis in first trimester extravillous trophoblasts from pregnancies at higher risk of developing preeclampsia. Am J Pathol. 2007;170(6):1903–9. doi:10.2353/ajpath.2007.070006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sharp AN, Heazell AE, Crocker IP, Mor G. Placental apoptosis in health and disease. Am J Reprod Immunol. 2010;64(3):159–69. doi:10.1111/j.1600-0897.2010.00837.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Prives C, Hall PA. The p53 pathway. J Pathol. 1999;187(1):112–26. doi:10.1002/(SICI)1096-9896(199901)187:1<112::AID-PATH250>3.0.CO;2-3.

    Article  CAS  PubMed  Google Scholar 

  10. Sharp AN, Heazell AE, Baczyk D, Dunk CE, Lacey HA, Jones CJ, et al. Preeclampsia is associated with alterations in the p53-pathway in villous trophoblast. PLoS One. 2014;9(1):e87621. doi:10.1371/journal.pone.0087621.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7(7A):1126–32.

    Article  CAS  PubMed  Google Scholar 

  12. Jones SN, Roe AE, Donehower LA, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995;378(6553):206–8. doi:10.1038/378206a0.

    Article  CAS  PubMed  Google Scholar 

  13. Meek DW. The p53 response to DNA damage. DNA Repair (Amst). 2004;3(8–9):1049–56. doi:10.1016/j.dnarep.2004.03.027.

    Article  CAS  Google Scholar 

  14. Gao Q, Zhu X, Chen J, Mao C, Zhang L, Xu Z. Upregulation of P53 promoted G1 arrest and apoptosis in human umbilical cord vein endothelial cells from preeclampsia. J Hypertens. 2016;34(7):1380–8. doi:10.1097/HJH.0000000000000944.

    Article  CAS  PubMed  Google Scholar 

  15. Berks D, Duvekot JJ, Steegers EA, Visser W. P53. Association between trombophilia and preeclampsia. Pregnancy hypertension. 2011;1(3–4):298. doi:10.1016/j.preghy.2011.08.114.

    CAS  PubMed  Google Scholar 

  16. Lucas Rosa Fraga MB. Polymorphisms of the apoptotic genes TP53 and MDM2 and preeclampsia development. Journal of Fertilization: In Vitro - IVF-Worldwide, Reproductive Medicine, Genetics & Stem Cell Biology. 2014;03(01). doi:10.4172/2375-4508.1000135.

  17. Busatto M FL, Boquett JA. Polymorphisms of the apoptotic genes TP53 and MDM2 and preeclampsia development. JFIV Reprod Med Genet. 2014;3(1).

  18. Lalonde ME, Ouimet M, Lariviere M, Kritikou EA, Sinnett D. Identification of functional DNA variants in the constitutive promoter region of MDM2. Human genomics. 2012;6:15. doi:10.1186/1479-7364-6-15.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ohmiya N, Taguchi A, Mabuchi N, Itoh A, Hirooka Y, Niwa Y, et al. MDM2 promoter polymorphism is associated with both an increased susceptibility to gastric carcinoma and poor prognosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(27):4434–40. doi:10.1200/JCO.2005.04.1459.

    Article  CAS  Google Scholar 

  20. Gaunt TR, Rodriguez S, Day IN. Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool ‘CubeX’. BMC bioinformatics. 2007;8:428. doi:10.1186/1471-2105-8-428.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta. 2009;30(6):473–82. doi:10.1016/j.placenta.2009.02.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mayhew TM. Villous trophoblast of human placenta: a coherent view of its turnover, repair and contributions to villous development and maturation. Histol Histopathol. 2001;16(4):1213–24.

    CAS  PubMed  Google Scholar 

  23. Longtine MS, Chen B, Odibo AO, Zhong Y, Nelson DM. Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR. Placenta. 2012;33(5):352–9. doi:10.1016/j.placenta.2012.01.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Myatt L. Review: reactive oxygen and nitrogen species and functional adaptation of the placenta. Placenta. 2010;31(Suppl):S66–9. doi:10.1016/j.placenta.2009.12.021.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Roberts JM, Escudero C. The placenta in preeclampsia. Pregnancy hypertension. 2012;2(2):72–83. doi:10.1016/j.preghy.2012.01.001.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516. doi:10.1080/01926230701320337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387(6630):296–9. doi:10.1038/387296a0.

    Article  CAS  PubMed  Google Scholar 

  28. Heazell AE, Lacey HA, Jones CJ, Huppertz B, Baker PN, Crocker IP. Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast. Placenta. 2008;29(2):175–86. doi:10.1016/j.placenta.2007.11.002.

    Article  CAS  PubMed  Google Scholar 

  29. Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M. A functional p53-responsive intronic promoter is contained within the human mdm2 gene. Nucleic Acids Res. 1995;23(14):2584–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119(5):591–602. doi:10.1016/j.cell.2004.11.022.

    Article  CAS  PubMed  Google Scholar 

  31. Xue Z, Zhu X, Teng Y. Relationship between murine double minute 2 (MDM2) T309G polymorphism and endometrial cancer risk: a meta-analysis. Medical science monitor : international medical journal of experimental and clinical research. 2016;22:3186–90.

    Article  Google Scholar 

  32. Lv J, Zhu B, Zhang L, Xie Q, Zhuo W. MDM2 SNP309 variation confers the susceptibility to hepatocellular cancer: a meta-analysis based on 4271 subjects. Int J Clin Exp Med. 2015;8(4):5822–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Salimi S, Hajizadeh A, Khodamian M, Pejman A, Fazeli K, Yaghmaei M. Age-dependent association of MDM2 promoter polymorphisms and uterine leiomyoma in South-East Iran: a preliminary report. J Obstet Gynaecol Res. 2015;41(5):729–34. doi:10.1111/jog.12625.

    Article  CAS  PubMed  Google Scholar 

  34. Fang Y, Kong B, Yang Q, Ma D, Qu X. The p53-HDM2 gene-gene polymorphism interaction is associated with the development of missed abortion. Hum Reprod. 2011;26(5):1252–8. doi:10.1093/humrep/der017.

    Article  CAS  PubMed  Google Scholar 

  35. Salimi S, Moudi B, Farajian Mashhadi F, Tavilani H, Hashemi M, Zand H, et al. Association of functional polymorphisms in FAS and FAS ligand genes promoter with pre-eclampsia. J Obstet Gynaecol Res. 2014;40(5):1167–73. doi:10.1111/jog.12327.

    Article  CAS  PubMed  Google Scholar 

  36. Orlando Junior IC, Tanaka SC, Balarin MA, da Silva SR, Pissetti CW. CASPASE-8 gene polymorphisms (rs13416436 and rs2037815) are not associated with preeclampsia development in Brazilian women. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. 2017:1–15. doi:10.1080/14767058.2017.1285882.

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Acknowledgements

The study was supported by the Research Center of Research Deputy in Zahedan University of Medical Sciences (Registered No. 1395.18).

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Correspondence to Abbas Mohammadpour-Gharehbagh.

Ethics declarations

Informed consent was obtained from all subjects, and the study protocol was approved by the Ethics Committee of Zahedan University of Medical Sciences and conducted in accordance with the Declaration of Helsinki.

Conflict of interest

The authors declare that they have no conflict of interest.

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Salimi, S., Mohammadpour-Gharehbagh, A., Rezaei, M. et al. The MDM2 promoter T309G polymorphism was associated with preeclampsia susceptibility. J Assist Reprod Genet 34, 951–956 (2017). https://doi.org/10.1007/s10815-017-0941-3

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  • DOI: https://doi.org/10.1007/s10815-017-0941-3

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