Molecular Biology Reports

, Volume 41, Issue 3, pp 1871–1877 | Cite as

p53 signaling pathway polymorphisms associated to recurrent pregnancy loss

  • L. R. Fraga
  • C. G. Dutra
  • J. A. Boquett
  • F. S. L. Vianna
  • R. O. Gonçalves
  • D. D. Paskulin
  • O. L. Costa
  • P. Ashton-Prolla
  • M. T. V. Sanseverino
  • L. Schuler-FacciniEmail author


The p53 protein is known for performing essential functions in the maintenance of genomic stability in somatic cells and prevention of tumor formation. Studies of the p53 signaling pathway have suggested associations between some polymorphisms and infertility, post-in vitro fertilization implantation failure and recurrent abortions. The TP53 Pro72Arg polymorphism has been implicated as a risk factor for recurrent pregnancy loss (RPL); however, the association is controversial. In this study, our objective was to evaluate selected polymorphisms in genes of the p53 signalling pathway [TP53 c.215G>C (Pro72Arg), MDM2 c.14+309T>G (SNP309) and LIF c.1414T>G in the region 3′ UTR] and determine their effect as risk factors for RPL. In a case–control study, we investigated 120 women with two or more pregnancy losses and 143 fertile control women reporting at least two live births and no history of pregnancy loss. When analyzed separately, the allele and genotype distributions of the polymorphisms in the two groups were not different. However, in a multivariate analysis adjusted for alcohol consumption, smoking, ethnicity, and number of pregnancies, the interaction between the genotypes TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) showed to be associated to RPL, increasing the risk for this condition (OR = 2.58, 95 % CI: 1.31–5.07, p = 0.006). In conclusion, our study indicates that the combination of TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) genotypes may be a risk factor for RPL.


MDM2 P53 Polymorphism Recurrent pregnancy loss Reproduction 



The authors would like to thank Dr. Sidia Maria Callegari Jacques for her assistance in the statistical analysis of the data. This work was supported by Instituto Nacional de Genética Médica Populacional (INAGEMP), Fundo de Apoio a Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre (FIPE-HCPA), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).


  1. 1.
    Rai R, Regan L (2006) Recurrent miscarriage. Lancet 368:601–611PubMedCrossRefGoogle Scholar
  2. 2.
    Branch DW, Gibson M, Silver RM (2010) Clinical practice. Recurrent miscarriage. N Engl J Med 363:1740–1747PubMedCrossRefGoogle Scholar
  3. 3.
    Pandey MK, Rani R, Agrawal S (2005) An update in recurrent spontaneous abortion. Arch Gynecol Obstet 272:95–108PubMedCrossRefGoogle Scholar
  4. 4.
    Toth B, Jeschke U, Rogenhofer N, Scholz C, Wurfel W, Thaler CJ, Makrigiannakis A (2010) Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 85:25–32PubMedCrossRefGoogle Scholar
  5. 5.
    Laurino MY, Bennett RL, Saraiya DS, Baumeister L, Doyle DL, Leppig K, Pettersen B, Resta R, Shields L, Uhrich S et al (2005) Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic Counselors. J Genet Couns 14:165–181PubMedCrossRefGoogle Scholar
  6. 6.
    Levine AJ, Hu W, Feng Z (2006) The P53 pathway: what questions remain to be explored? Cell Death Differ 13:1027–1036PubMedCrossRefGoogle Scholar
  7. 7.
    Hu W (2009) The role of p53 gene family in reproduction. Cold Spring Harb Perspect Biol 1:a001073PubMedCrossRefGoogle Scholar
  8. 8.
    Brady CA, Attardi LD (2010) p53 at a glance. J Cell Sci 123(Pt 15):2527–2532PubMedCrossRefGoogle Scholar
  9. 9.
    Hu W, Feng Z, Teresky AK, Levine AJ (2007) p53 regulates maternal reproduction through LIF. Nature 450:721–724PubMedCrossRefGoogle Scholar
  10. 10.
    Brooks CL, Gu W (2006) p53 ubiquitination: MDM2 and beyond. Mol Cell 21(3):307–315PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602PubMedCrossRefGoogle Scholar
  12. 12.
    Brooks CL, Li M, Hu M, Shi Y, Gu W (2007) The p53–MDM2–HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene 26(51):7262–7266PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Kang HJ, Feng Z, Sun Y, Atwal G, Murphy ME, Rebbeck TR, Rosenwaks Z, Levine AJ, Hu W (2009) Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci USA 106:9761–9766PubMedCrossRefGoogle Scholar
  14. 14.
    Firouzabadi RD, Ghasemi N, Rozbahani MA, Tabibnejad N (2009) Association of p53 polymorphism with ICSI/IVF failure and recurrent pregnancy loss. Aust N Z J Obstet Gynaecol 49:216–219PubMedCrossRefGoogle Scholar
  15. 15.
    Tagliani-Ribeiro A, Paskulin DD, Oliveira M, Zagonel-Oliveira M, Longo D, Ramallo V, Ashton-Prolla P, Saraiva-Pereira ML, Fagundes NJ, Schuler-Faccini L et al (2012) High twinning rate in Candido Godoi: a new role for p53 in human fertility. Hum Reprod 27:2866–2871PubMedCrossRefGoogle Scholar
  16. 16.
    Fang Y, Kong B, Yang Q, Ma D, Qu X (2011) The p53-HDM2 gene–gene polymorphism interaction is associated with the development of missed abortion. Hum Reprod 26:1252–1258PubMedCrossRefGoogle Scholar
  17. 17.
    Coulam CB, Kay C, Jeyendran RS (2006) Role of p53 codon 72 polymorphism in recurrent pregnancy loss. Reprod Biomed Online 12:378–382PubMedCrossRefGoogle Scholar
  18. 18.
    Kaare M, Butzow R, Ulander VM, Kaaja R, Aittomaki K, Painter JN (2009) Study of p53 gene mutations and placental expression in recurrent miscarriage cases. Reprod Biomed Online 18:430–435PubMedCrossRefGoogle Scholar
  19. 19.
    Pietrowski D, Bettendorf H, Riener EK, Keck C, Hefler LA, Huber JC, Tempfer C (2005) Recurrent pregnancy failure is associated with a polymorphism in the p53 tumour suppressor gene. Hum Reprod 20:848–851PubMedCrossRefGoogle Scholar
  20. 20.
    Buchman VL, Chumakov PM, Ninkina NN, Samarina OP, Georgiev GP (1988) A variation in the structure of the protein-coding region of the human p53 gene. Gene 70:245–252PubMedCrossRefGoogle Scholar
  21. 21.
    Dumont P, Leu JI, Della Pietra AC 3rd, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33(3):357–365PubMedCrossRefGoogle Scholar
  22. 22.
    Giess R, Tanasescu I, Steck T, Sendtner M (1999) Leukaemia inhibitory factor gene mutations in infertile women. Mol Hum Reprod 5:581–586PubMedCrossRefGoogle Scholar
  23. 23.
    Ishida R, Ezura Y, Iwasaki H, Nakazawa I, Kajita M, Kodaira M, Ito H, Emi M (2001) Linkage disequilibrium and haplotype analysis among four novel single-nucleotide polymorphisms in the human leukemia inhibitory factor (LIF) gene. J Hum Genet 46:557–559PubMedCrossRefGoogle Scholar
  24. 24.
    Daher S, Shulzhenko N, Morgun A, Mattar R, Rampim GF, Camano L, DeLima MG (2003) Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J Reprod Immunol 58:69–77PubMedCrossRefGoogle Scholar
  25. 25.
    Finan RR, Al-Irhayim Z, Mustafa FE, Al-Zaman I, Mohammed FA, Al-Khateeb GM, Madan S, Issa AA, Almawi WY (2010) Tumor necrosis factor-alpha polymorphisms in women with idiopathic recurrent miscarriage. J Reprod Immunol 84:186–192PubMedCrossRefGoogle Scholar
  26. 26.
    Prigoshin N, Tambutti M, Larriba J, Gogorza S, Testa R (2004) Cytokine gene polymorphisms in recurrent pregnancy loss of unknown cause. Am J Reprod Immunol 52:36–41PubMedCrossRefGoogle Scholar
  27. 27.
    Su MT, Lin SH, Lee IW, Chen YC, Kuo PL (2011) Association of polymorphisms/haplotypes of the genes encoding vascular. Hum Reprod 26:758–764PubMedCrossRefGoogle Scholar
  28. 28.
    Tempfer C, Unfried G, Zeillinger R, Hefler L, Nagele F, Huber JC (2001) Endothelial nitric oxide synthase gene polymorphism in women with idiopathic recurrent miscarriage. Hum Reprod 16:1644–1647PubMedCrossRefGoogle Scholar
  29. 29.
    Marcel V, Palmero EI, Falagan-Lotsch P, Martel-Planche G, Ashton-Prolla P, Olivier M, Brentani RR, Hainaut P, Achatz MI (2009) TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni. J Med Genet 46:766–772PubMedCrossRefGoogle Scholar
  30. 30.
    Thurow HS, Haack R, Hartwig FP, Oliveira IO, Dellagostin OA, Gigante DP, Horta BL, Collares T, Seixas FK (2011) TP53 gene polymorphism: importance to cancer, ethnicity and birth weight in a Brazilian cohort. J Biosci 36:823–831PubMedCrossRefGoogle Scholar
  31. 31.
    Salvioli S, Bonafe M, Barbi C, Storci G, Trapassi C, Tocco F, Gravina S, Rossi M, Tiberi L, Mondello C et al (2005) p53 codon 72 alleles influence the response to anticancer drugs in cells from aged people by regulating the cell cycle inhibitor p21WAF1. Cell Cycle 4:1264–1271PubMedCrossRefGoogle Scholar
  32. 32.
    Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL (1996) Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci USA 93:3115–3120PubMedCrossRefGoogle Scholar
  33. 33.
    Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, Abbondanzo SJ (1992) Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359:76–79PubMedCrossRefGoogle Scholar
  34. 34.
    Feng Z, Zhang C, Kang HJ, Sun Y, Wang H, Naqvi A, Frank AK, Rosenwaks Z, Murphy ME, Levine AJ et al (2011) Regulation of female reproduction by p53 and its family members. FASEB J 25:2245–2255PubMedCrossRefGoogle Scholar
  35. 35.
    Kay C, Jeyendran RS, Coulam CB (2006) p53 tumour suppressor gene polymorphism is associated with recurrent implantation. Reprod Biomed Online 13:492–496PubMedCrossRefGoogle Scholar
  36. 36.
    Norimura T, Nomoto S, Katsuki M, Gondo Y, Kondo S (1996) p53-dependent apoptosis suppresses radiation-induced teratogenesis. Nat Med 2:577–580PubMedCrossRefGoogle Scholar
  37. 37.
    Amsterdam A, Keren-Tal I, Aharoni D, Dantes A, Land-Bracha A, Rimon E, Sasson R, Hirsh L (2003) Steroidogenesis and apoptosis in the mammalian ovary. Steroids 68:861–867PubMedCrossRefGoogle Scholar
  38. 38.
    Halperin R, Peller S, Sandbank J, Bukovsky I, Schneider D (2000) Expression of the p53 gene and apoptosis in gestational trophoblastic disease. Placenta 21:58–62PubMedCrossRefGoogle Scholar
  39. 39.
    Watson ED, Cross JC (2005) Development of structures and transport functions in the mouse placenta. Physiology (Bethesda) 20:180–193CrossRefGoogle Scholar
  40. 40.
    Cohen M, Meisser A, Haenggeli L, Irminger-Finger I, Bischof P (2007) Status of p53 in first-trimester cytotrophoblastic cells. Mol Hum Reprod 13:111–116PubMedCrossRefGoogle Scholar
  41. 41.
    Marzusch K, Ruck P, Horny HP, Dietl J, Kaiserling E (1995) Expression of the p53 tumour suppressor gene in human placenta: an immunohistochemical study. Placenta 16:101–104PubMedCrossRefGoogle Scholar
  42. 42.
    Cohen M, Wuillemin C, Irion O, Bischof P (2008) Regulation of MMP-9 by p53 in first trimester cytotrophoblastic cells. Hum Reprod 23:2273–2281PubMedCrossRefGoogle Scholar
  43. 43.
    Wei P, Jin X, Zhang XS, Hu ZY, Han CS, Liu YX (2005) Expression of Bcl-2 and p53 at the fetal-maternal interface of rhesus monkey. Reprod Biol Endocrinol 3:4PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Halperin R, Peller S, Rotschild M, Bukovsky I, Schneider D (2000) Placental apoptosis in normal and abnormal pregnancies. Gynecol Obstet Invest 50:84–87PubMedCrossRefGoogle Scholar
  45. 45.
    Minas V, Jeschke U, Kalantaridou SN, Richter DU, Reimer T, Mylonas I, Friese K, Makrigiannakis A (2007) Abortion is associated with increased expression of FasL in decidual leukocytes. Mol Hum Reprod 13:663–673PubMedCrossRefGoogle Scholar
  46. 46.
    Veljkovic Vujaklija D, Sucic S, Gulic T, Dominovic M, Rukavina D (2012) Cell death mechanisms at the maternal-fetal interface: insights into the role of granulysin. Clin Dev Immunol 2012:180272PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Savion S, Lepsky E, Orenstein H, Carp H, Shepshelovich J, Torchinsky A, Fein A, Toder V (2002) Apoptosis in the uterus of mice with pregnancy loss. Am J Reprod Immunol 47:118–127PubMedCrossRefGoogle Scholar
  48. 48.
    Hu C, Smith SD, Pang L, Sadovsky Y, Nelson DM (2006) Enhanced basal apoptosis in cultured term human cytotrophoblasts is associated with a higher expression and physical interaction of p53 and Bak. Placenta 27:978–983PubMedCrossRefGoogle Scholar
  49. 49.
    Levy R, Smith SD, Yusuf K, Huettner PC, Kraus FT, Sadovsky Y, Nelson DM (2002) Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is. Am J Obstet Gynecol 186:1056–1061PubMedCrossRefGoogle Scholar
  50. 50.
    Yamauchi H, Katayama K, Ueno M, He XJ, Mikami T, Uetsuka K, Doi K, Nakayama H (2007) Essential role of p53 in trophoblastic apoptosis induced in the developing rodent. Apoptosis 12:1743–1754PubMedCrossRefGoogle Scholar
  51. 51.
    Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M, Munne S (2012) Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertil Steril 98:675–680PubMedCrossRefGoogle Scholar
  52. 52.
    Quenby S, Vince G, Farquharson R, Aplin J (2002) Recurrent miscarriage: a defect in nature’s quality control? Hum Reprod 17:1959–1963PubMedCrossRefGoogle Scholar
  53. 53.
    Leon PM, Campos VF, Thurow HS, Hartwig FP, Selau LP, Dellagostin OA, Neto JB, Deschamps JC, Seixas FK, Collares T (2012) Association between single nucleotide polymorphisms in p53 and abortion in Thoroughbred mares. Vet J 193:573–575PubMedCrossRefGoogle Scholar
  54. 54.
    Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ (2002) Moderate alcohol intake in pregnancy and the risk of spontaneous abortion. Alcohol Alcohol 37:87–92PubMedCrossRefGoogle Scholar
  55. 55.
    Kumar S (2011) Occupational, environmental and lifestyle factors associated with spontaneous. Reprod Sci 18:915–930PubMedCrossRefGoogle Scholar
  56. 56.
    Lindbohm ML, Sallmen M, Taskinen H (2002) Effects of exposure to environmental tobacco smoke on reproductive health. Scand J Work Environ Health 28(Suppl 2):84–96PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • L. R. Fraga
    • 1
  • C. G. Dutra
    • 1
  • J. A. Boquett
    • 1
  • F. S. L. Vianna
    • 1
    • 2
  • R. O. Gonçalves
    • 3
  • D. D. Paskulin
    • 1
  • O. L. Costa
    • 3
  • P. Ashton-Prolla
    • 1
    • 2
    • 4
  • M. T. V. Sanseverino
    • 2
    • 4
  • L. Schuler-Faccini
    • 1
    • 2
    • 4
    Email author
  1. 1.Post-Graduation Program in Genetics and Molecular Biology, Departament of Genetics, Biosciences InstituteUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  2. 2.INAGEMP – Instituto Nacional de Genética Médica PopulacionalUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Post-Graduation Program in Biotechnology in Health and Investigative Medicine and Department of Obstetrics, Gynecology and Human Reproduction, Medical SchoolUniversidade Federal da Bahia (UFBA)SalvadorBrazil
  4. 4.Medical Genetics ServiceHospital de Clínicas de Porto AlegrePorto AlegreBrazil

Personalised recommendations