Skip to main content

Advertisement

SpringerLink
Log in

Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications

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

Abstract

Purpose

The aim of this study was to confirm the associated M2/ANXA5 carrier risk in women with placenta-mediated pregnancy complications (PMPC) and to test their male partners for such association. Further analysis evaluated the influence of maternal vs. paternal M2 alleles on miscarriage.

Methods

Two hundred eighty-eight couples with preeclampsia (PE), intrauterine growth restriction (IUGR), or premature birth (PB) were recruited (n = 96 of each phenotype). The prevalence of the M2 haplotype was compared to two control cohorts. They included a group of women with a history of normal pregnancy without gestational pathology (Munich controls, n = 94) and a random population sample (PopGen controls, n = 533).

Results

Significant association of M2 haplotype and pregnancy complications was confirmed for women and for couples, where prevalence was elevated from 15.4 to 23.8% (p < 0.001). Post hoc analyses demonstrated an association for IUGR and PB individually. A strong link between previous miscarriages and M2 carrier status was identified which may explain the predisposition to placental pregnancy complication. M2/ANXA5 appears to be a risk factor for adverse pregnancy outcomes related, but not limited to miscarriages, with similar prevalence in women and their male partners.

Conclusion

These findings support the proposed physiological function of ANXA5 as an embryonic anticoagulant that appears deficient in contiguous specter of thrombophilia-related pregnancy complications culminating more frequently in miscarriage in a maternal M2 carrier background.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Younis JS, Samueloff A. Gestational vascular complications. Best Pract Res Clin Haematol. 2003;16:135–51.

    Article  PubMed  Google Scholar 

  2. Grandone E, Margaglione M. Inherited thrombophilia and gestational vascular complications. Best Pract Res Clin Haematol. 2003;16:321–32.

    Article  PubMed  Google Scholar 

  3. Tiscia G, Colaizzo D, Chinni E, et al. Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications. Thromb Haemost. 2009;102:309–13.

    CAS  PubMed  Google Scholar 

  4. Bogdanova N, Markoff A. Hereditary thrombophilic risk factors for recurrent pregnancy loss. J Community Genet. 2010;1:47–53.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361:901–8.

    Article  PubMed  Google Scholar 

  6. Rodger MA, Betancourt MT, Clark P, et al. The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med. 2010;7:e1000292.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bogdanova N, Horst J, Chlystun M, et al. A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum Mol Genet. 2007;16:573–8.

    Article  CAS  PubMed  Google Scholar 

  8. Tiscia G, Colaizzo D, Favuzzi G, et al. The M2 haplotype in the ANXA5 gene is an independent risk factor for idiopathic small-for-gestational age newborns. Mol Hum Reprod. 2012;18:510–3.

    Article  CAS  PubMed  Google Scholar 

  9. Tüttelmann F, Ivanov P, Dietzel C, et al. Further insights into the role of the annexin A5 M2 haplotype as recurrent pregnancy loss factor, assessing timing of miscarriage and partner risk. Fertil Steril. 2013;100:1321–5.

    Article  PubMed  Google Scholar 

  10. Demetriou C, Abu-Amero S, White S, et al. Investigation of the Annexin A5 M2 haplotype in 500 white European couples who have experienced recurrent spontaneous abortion. Reprod BioMed Online. 2015;31:681–8.

    Article  CAS  PubMed  Google Scholar 

  11. Miyamura H, Nishizawa H, Ota S, et al. Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss. Mol Hum Reprod. 2011;17:447–52.

    Article  CAS  PubMed  Google Scholar 

  12. Ota S, Miyamura H, Nishizawa H, et al. Contribution of fetal ANXA5 gene promoter polymorphisms to the onset of pre-eclampsia. Placenta. 2013;34:1202–10.

    Article  CAS  PubMed  Google Scholar 

  13. Thean Hock T, Bogdanova N, Kai Cheen A, et al. M2/ANXA5 haplotype as a predisposition factor in Malay women and couples experiencing recurrent spontaneous abortion: a pilot study. Reprod BioMed Online. 2015;30:431–9.

    Article  Google Scholar 

  14. Ang KC, Kathirgamanathan S, Ch'ng ES, et al. Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population. J Assist Reprod Genet. 2017;34:517–24.

    Article  PubMed  Google Scholar 

  15. Tiscia GL, Dørum E, Myklebust CF, Grandone E, Sandset PM, Skretting G. Functional characterization of annexin A5 gene promoter allelic variants. Thromb Res. 2016;144:93–9.

    Article  CAS  PubMed  Google Scholar 

  16. Chinni E, Tiscia GL, Colaizzo D, Vergura P, Margaglione M, Grandone E. Annexin V expression in human placenta is influenced by the carriership of the common haplotype M2. Fertil Steril. 2009;91:940–2.

    Article  CAS  PubMed  Google Scholar 

  17. Markoff A, Gerdes S, Feldner S, Bogdanova N, Gerke V, Grandone E. Reduced allele specific annexin A5 mRNA levels in placentas carrying the M2/ANXA5 allele. Placenta. 2010;31:937–40.

    Article  CAS  PubMed  Google Scholar 

  18. Krikun G, Lockwood CJ, Wu XX, et al. The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: immunolocalization and in vitro regulation. Placenta. 1994;15:601–12.

    Article  CAS  PubMed  Google Scholar 

  19. Rand JH, Wu XX, Andree HA, et al. Pregnancy loss in the antiphospholipid-antibody syndrome—a possible thrombogenic mechanism. N Engl J Med. 1997;337:154–60.

    Article  CAS  PubMed  Google Scholar 

  20. Rogenhofer N, Engels L, Bogdanova N, Tüttelmann F, Markoff A, Thaler CJ. Paternal and maternal carriage of the annexin A5 M2 haplotype are equal risk factors for recurrent pregnancy loss: a pilot study. Fertil Steril. 2012;98:383–8.

    Article  CAS  PubMed  Google Scholar 

  21. ACOG Committee. On practice bulletins-obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol. 2002;99:159–67.

    Article  Google Scholar 

  22. Lausman A, Kingdom J, Maternal Fetal Medicine Committee, et al. Intrauterine growth restriction: screening, diagnosis, and management. J Obstet Gynaecol Can. 2013;35:741–57.

    Article  PubMed  Google Scholar 

  23. Unterscheider J, Daly S, Geary MP, et al. Definition and management of fetal growth restriction: a survey of contemporary attitudes. Eur J Obstet Gynecol Reprod Biol. 2014;174:41–5.

    Article  PubMed  Google Scholar 

  24. Wise J. NICE guideline aims to cut premature birth rates. BMJ. 2015;351:h6253.

    Article  PubMed  Google Scholar 

  25. National Collaborating Centre for Women’s and Children’s Health (UK). Preterm labour and birth. London: National Institute for Health and Care Excellence (UK); 2015.

    Google Scholar 

  26. Rotterdam ESHRE⁄ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.

    Google Scholar 

  27. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.

    Article  CAS  PubMed  Google Scholar 

  28. Krawczak M, Nikolaus S, von Eberstein H, Croucher PJ, El Mokhtari NE, Schreiber S. PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community Genet. 2006;9:55–61.

    PubMed  Google Scholar 

  29. Hothorn T, Bretz F, Westfall P. Simultaneous inference in general parametric models. Biom J. 2008;50:346–63.

    Article  PubMed  Google Scholar 

  30. Hossain N, Paidas MJ. Inherited thrombophilia: diagnosis and anticoagulation treatment in pregnancy. Clin Lab Med. 2013;33:377–90.

    Article  PubMed  Google Scholar 

  31. Silva JF, Serakides R. Intrauterine trophoblast migration: a comparative view of humans and rodents. Cell Adhes Migr. 2016;10:88–110.

    Article  CAS  Google Scholar 

  32. Dusse LM, Rios DR, Pinheiro MB, Cooper AJ, Lwaleed BA. Pre-eclampsia: relationship between coagulation, fibrinolysis and inflammation. Clin Chim Acta. 2011;412:17–21.

    Article  CAS  PubMed  Google Scholar 

  33. Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ. 1998;31:1343–7.

    Article  Google Scholar 

  34. Vefring H, Lie RT, ØDegård R, Mansoor MA, Nilsen ST. Maternal and fetal variants of genetic thrombophilias and the risk of preeclampsia. Epidemiology. 2004;15:317–22.

    Article  PubMed  Google Scholar 

  35. Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. BMJ. 1997;315:32–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. ACOG Committee. On practice bulletins. ACOG practice bulletin no. 77. Screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109:217–27.

    Article  Google Scholar 

  37. Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod. 1996;11:2217–22.

    Article  CAS  PubMed  Google Scholar 

  38. Fishel S, Baker D, Elson J, et al. Precision medicine in assisted conception: a multicenter observational treatment cohort study of the annexin A5 M2 haplotype as a biomarker for antithrombotic treatment to improve pregnancy outcome. EBioMedicine. 2016;10:298–304.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to express their gratitude to all patients and to their partners, who contributed genetic material for this study.

Funding

AM was supported by a PI grant of the German Research Community, DFG, MA-6288/1-1.

Author information

Authors and Affiliations

  1. Division of Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, Klinikum der Ludwig-Maximilians-Universität, Munich, Campus Grosshadern, D-81377, Munich, Germany

    Nina Rogenhofer, Lara R. M. Nienaber & Christian J. Thaler

  2. Insititute of Human Genetics, UKM and WWU Muenster, Vesaliusweg 12-14, 48149, Muenster, Germany

    Lea C. Amshoff, Nadia Bogdanova, Peter Wieacker & Arseni Markoff

  3. Clinical Trial Centre, University of Leipzig, 04017, Leipzig, Germany

    David Petroff

Authors
  1. Nina Rogenhofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lara R. M. Nienaber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lea C. Amshoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadia Bogdanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Petroff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Wieacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian J. Thaler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arseni Markoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arseni Markoff.

Ethics declarations

The present genetic association study complied with the ethical guidelines of the institutions involved and was approved of the Review Board of the University Munich (IRB 209-12). Informed consent was obtained from all subjects examined.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rogenhofer, N., Nienaber, L.R.M., Amshoff, L.C. et al. Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications. J Assist Reprod Genet 35, 157–163 (2018). https://doi.org/10.1007/s10815-017-1041-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-017-1041-0

Keywords

Search

Navigation