Advertisement

Reproductive Sciences

, Volume 19, Issue 5, pp 547–554 | Cite as

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

  • Prabha H. Andraweera
  • Gustaaf A. Dekker
  • Steven D. Thompson
  • Claire T. RobertsEmail author
Original Articles

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.

Keywords

KDR polymorphism preeclampsia small-for-gestational-age infants 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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.CrossRefGoogle Scholar
  2. 2.
    Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–799.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 9.
    Ferrara N, Gerber HP, Lecouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 21.
    Harlap S, Paltiel O, Deutsch L, et al. Paternal age and preeclampsia. Epidemiology. 2002;13(6):660–667.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 24.
    Mccowan L, Horgan RP. Risk factors for small for gestational age infants. Best Pract Res Clin Obstet Gynaecol. 2009;23(6):779–793.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 28.
    Magnus P, Gjessing HK, Skrondal A, Skjaerven R. Paternal contribution to birth weight. J Epidemiol Community Health. 2001;55(12):873–877.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 31.
    Lucas A. Role of nutritional programming in determining adult morbidity. Arch Dis Child. 1994;71(4):288–290.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar

Copyright information

© Society for Reproductive Investigation 2012

Authors and Affiliations

  • Prabha H. Andraweera
    • 1
    • 2
  • Gustaaf A. Dekker
    • 1
    • 3
  • Steven D. Thompson
    • 1
  • Claire T. Roberts
    • 1
    Email author
  1. 1.Discipline of Obstetrics and Gynaecology, Robinson InstituteUniversity of AdelaideAustralia
  2. 2.Human Genetics Unit, Faculty of MedicineUniversity of ColomboSri Lanka
  3. 3.Women’s and Children’s DivisionLyell McEwin Hospital, Elizabeth ValeSouth Australia

Personalised recommendations