Skip to main content

Advertisement

SpringerLink
Log in

Single-Nucleotide Polymorphisms in the KDR Gene in Pregnancies Complicated by Gestational Hypertensive Disorders and Small-for-Gestational-Age Infants

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Introduction

Pregnancies complicated by preeclampsia and small-for-gestational-age (SGA) infants share placental vascular abnormalities and both disorders confer increased risk of later life coronary artery disease. Kinase insert domain receptor (KDR) is the main receptor for vascular endothelial growth factor A, a potent angiogenic factor which regulates the development of the placental vasculature. Two polymorphisms in KDR (-604T/C and Val297Ile) are known to be associated with coronary artery disease. We investigated the association of these polymorphisms with preeclampsia, gestational hypertension, and SGA infants.

Method

Nulliparous pregnant women, their partners, and infants were recruited to a prospective cohort study (n = 1169). Doppler ultrasound of the uterine and umbilical arteries was performed at 20 weeks of gestation. Preeclampsia, gestational hypertension, and SGA were defined according to international guidelines. DNA extracted from peripheral venous or cord blood was genotyped using the Sequenom MassARRAY system. Multivariable logistic regression was used to compare the odds for the pregnancy complications between the genotype groups adjusting for potential confounders.

Results

Among 937 Caucasian pregnancies, 427 (45.6%) were uncomplicated, 75 (8.0%) developed preeclampsia, 102 (10.9%) developed gestational hypertension, and 72 (7.7%) had SGA infants in the absence of maternal hypertensive disease. Paternal and neonatal KDR-604T/C was associated with preeclampsia (adjusted odds ratio [aOR] 1.6, 95% confidence interval [CI] 1.0–3.0 and aOR 2.2, 95% CI 1.0–4.4), SGA (aOR 1.9, 95% CI 1.1–3.3 and aOR 2.2, 95% CI 1.2–3.9), and SGA with abnormal Doppler (aOR 2.7, 95% CI 1.2–5.9 and aOR 3.2, 95% CI 1.2–5.9).

Conclusion

Paternal and neonatal carriage of the KDR-604T/C polymorphism is associated with the risk of preeclampsia and SGA infants.

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. Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of preeclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2011;25(4):391–403.

    Article  Google Scholar 

  2. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–799.

    Article  Google Scholar 

  3. Mcdonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J. 2008;156(5):918–930.

    Article  Google Scholar 

  4. Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke. 2009;40(4):1176–1180.

    Article  Google Scholar 

  5. Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990;301(6746):259–262.

    Article  CAS  Google Scholar 

  6. Mckeigue PM, Lithell HO, Leon DA. Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia. 1998;41(10):1133–1138.

    Article  CAS  Google Scholar 

  7. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;2(8663):577–580.

    Article  CAS  Google Scholar 

  8. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol. 1986;93(10):1049–1059.

    Article  CAS  Google Scholar 

  9. Ferrara N, Gerber HP, Lecouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676.

    Article  CAS  Google Scholar 

  10. Charnock-Jones DS, Kaufmann P, Mayhew TM. Aspects of human fetoplacental vasculogenesis and angiogenesis. I. Molecular regulation. Placenta. 2004;25(2–3):103–113.

    Article  CAS  Google Scholar 

  11. Lash GE, Schiessl B, Kirkley M, et al. Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol. 2006;80(3):572–580.

    Article  CAS  Google Scholar 

  12. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535):62–66.

    Article  CAS  Google Scholar 

  13. Wang Y, Zheng Y, Zhang W, et al. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007;50(8):760–767.

    Article  CAS  Google Scholar 

  14. Zhang W, Sun K, Zhen Y, et al. VEGF receptor-2 variants are associated with susceptibility to stroke and recurrence. Stroke. 2009;40(8):2720–2726.

    Article  CAS  Google Scholar 

  15. Mccowan LM, Dekker GA, Chan E, et al. SCOPE consortium Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study. BMJ. 2009;338:bl081.

    Article  Google Scholar 

  16. Groom KM, North RA, Stone PR, et al. SCOPE consortium. Patterns of change in uterine artery Doppler studies between 20 and 24 weeks of gestation and pregnancy outcomes. Obstet Gynecol. 2009;113(2 pt 1):332–338.

    Article  Google Scholar 

  17. Brown MA, Hague WM, Higgins J, et al. Australasian Society of the Study of Hypertension in Pregnancy. The detection, investigation and management of hypertension in pregnancy: full consensus statement. Aust N Z J Obstet Gynaecol. 2000;40(2):139–155.

    Article  CAS  Google Scholar 

  18. Mccowan L, Stewart AW, Francis A, Gardosi J. A customised birthweight centile calculator developed for a New Zealand population. Aust N Z J Obstet Gynaecol. 2004; 44(5):428–431.

    Article  Google Scholar 

  19. Sullivan KM, Mannucci A, Kimpton CP, Gill P. A rapid and quantitative DNA sex test: fluorescence-based PCR analysis of X-Y homologous gene amelogenin. Biotechniques. 1993;15(4):636–638, 640–641.

    CAS  PubMed  Google Scholar 

  20. North RA, Mccowan LM, Dekker GA, et al. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort. BMJ. 2011;342:d1875.

    Article  Google Scholar 

  21. Harlap S, Paltiel O, Deutsch L, et al. Paternal age and preeclampsia. Epidemiology. 2002;13(6):660–667.

    Article  Google Scholar 

  22. Mccowan LM, North RA, Kho EM, et al. Paternal contribution to small for gestational age babies: a multicenter prospective study. Obesity (Silver Spring). 2011;19(5):1035–1039.

    Article  Google Scholar 

  23. Mccowan LM, Roberts CT, Dekker GA, et al: SCOPE consortium. Risk factors for small-for-gestational-age infants by customised birthweight centiles: data from an international prospective cohort study. BJOG. 2010;117(13):1599–1607.

    Article  CAS  Google Scholar 

  24. Mccowan L, Horgan RP. Risk factors for small for gestational age infants. Best Pract Res Clin Obstet Gynaecol. 2009;23(6):779–793.

    Article  Google Scholar 

  25. Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of preeclampsia: population based study. BMJ. 1998;316(7141):1343–1347.

    Article  CAS  Google Scholar 

  26. Esplin MS, Fausett MB, Fraser A, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med. 2001;344(12):867–872.

    Article  CAS  Google Scholar 

  27. Klebanoff MA, Mednick BR, Schulsinger C, Secher NJ, Shiono PH. Father’s effect on infant birth weight. Am J Obstet Gynecol. 1998;178(5):1022–1026.

    Article  CAS  Google Scholar 

  28. Magnus P, Gjessing HK, Skrondal A, Skjaerven R. Paternal contribution to birth weight. J Epidemiol Community Health. 2001;55(12):873–877.

    Article  CAS  Google Scholar 

  29. Jaquet D, Swaminathan S, Alexander GR, et al. Significant paternal contribution to the risk of small for gestational age. BJOG. 2005;112(2):153–159.

    Article  Google Scholar 

  30. Jeyabalan A, Powers RW, Clifton RG, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Effect of smoking on circulating angiogenic factors in high risk pregnancies. PLoS ONE. 2010;5(10):e13270.

    Article  Google Scholar 

  31. Lucas A. Role of nutritional programming in determining adult morbidity. Arch Dis Child. 1994;71(4):288–290.

    Article  CAS  Google Scholar 

  32. Thornburg KL, O’tierney PF, Louey S. Review: the placenta is a programming agent for cardiovascular disease. Placenta. 2010;31(suppl 1):S54–S59.

    Article  Google Scholar 

  33. Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14(11):1236–1246.

    Article  CAS  Google Scholar 

  34. Walter JW, North PE, Waner M, et al. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer. 2002;33(3):295–303.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Discipline of Obstetrics and Gynaecology, Robinson Institute, University of Adelaide, Australia

    Prabha H. Andraweera MBBS, Gustaaf A. Dekker FRANZCOG, PhD, Steven D. Thompson BHthSc & Claire T. Roberts PhD

  2. Human Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka

    Prabha H. Andraweera MBBS

  3. Women’s and Children’s Division, Lyell McEwin Hospital, Elizabeth Vale, South Australia

    Gustaaf A. Dekker FRANZCOG, PhD

Authors
  1. Prabha H. Andraweera MBBS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gustaaf A. Dekker FRANZCOG, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven D. Thompson BHthSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire T. Roberts PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claire T. Roberts PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Andraweera, P.H., Dekker, G.A., Thompson, S.D. et al. Single-Nucleotide Polymorphisms in the KDR Gene in Pregnancies Complicated by Gestational Hypertensive Disorders and Small-for-Gestational-Age Infants. Reprod. Sci. 19, 547–554 (2012). https://doi.org/10.1177/1933719111428520

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719111428520

Keywords

Search

Navigation