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.
Similar content being viewed by others
References
Bulletins--Obstetrics ACoP. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99(1):159–167.
Zhang J, Zeisler J, Hatch MC, Berkowitz G. Epidemiology of pregnancy-induced hypertension. Epidemiol Rev. 1997;19(2):218–32.
Carty DM, Delles C, Dominiczak AF. Preeclampsia and future maternal health. J Hypertens. 2010;28(7):1349–55. doi:10.1097/HJH.0b013e32833a39d0.
Dekker G, Sukcharoen N. Etiology of preeclampsia: an update. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2004;87(Suppl 3):S96–103.
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.
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.
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.
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.
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.
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.
Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7(7A):1126–32.
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.
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.
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.
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.
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.
Busatto M FL, Boquett JA. Polymorphisms of the apoptotic genes TP53 and MDM2 and preeclampsia development. JFIV Reprod Med Genet. 2014;3(1).
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.
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.
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.
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.
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.
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.
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.
Roberts JM, Escudero C. The placenta in preeclampsia. Pregnancy hypertension. 2012;2(2):72–83. doi:10.1016/j.preghy.2012.01.001.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516. doi:10.1080/01926230701320337.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgements
The study was supported by the Research Center of Research Deputy in Zahedan University of Medical Sciences (Registered No. 1395.18).
Author information
Authors and Affiliations
Corresponding author
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.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-017-0941-3