Pathogenesis of preeclampsia: the genetic component

Francisco J Valenzuela, Alejandra Pérez-Sepúlveda, María J Torres, Paula Correa, Gabriela M Repetto, Sebastián E Illanes, Francisco J Valenzuela, Alejandra Pérez-Sepúlveda, María J Torres, Paula Correa, Gabriela M Repetto, Sebastián E Illanes

Abstract

Preeclampsia (PE) is one of the main causes of maternal and fetal morbidity and mortality in the world, causing nearly 40% of births delivered before 35 weeks of gestation. PE begins with inadequate trophoblast invasion early in pregnancy, which produces an increase in oxidative stress contributing to the development of systemic endothelial dysfunction in the later phases of the disease, leading to the characteristic clinical manifestation of PE. Numerous methods have been used to predict the onset of PE with different degrees of efficiency. These methods have used fetal/placental and maternal markers in different stages of pregnancy. From an epidemiological point of view, many studies have shown that PE is a disease with a strong familiar predisposition, which also varies according to geographical, socioeconomic, and racial features, and this information can be used in the prediction process. Large amounts of research have shown a genetic association with a multifactorial polygenic inheritance in the development of this disease. Many biological candidate genes and polymorphisms have been examined in their relation with PE. We will discuss the most important of them, grouped by the different pathogenic mechanisms involved in PE.

References

    1. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. British Medical Journal. 2007;335(7627):974–977.
    1. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. American Heart Journal. 2008;156(5):918–930.
    1. Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort. Hypertension. 2010;56(1):166–171.
    1. Ness RB, Roberts JM. Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications. American Journal of Obstetrics & Gynecology. 1996;175(5):1365–1370.
    1. Borzychowski AM, Sargent IL, Redman CWG. Inflammation and pre-eclampsia. Seminars in Fetal and Neonatal Medicine. 2006;11(5):309–316.
    1. Redman CW. Current topic: PE and the placenta. Placenta. 1991;12(4):301–308.
    1. Aplin JD. Implantation, trophoblast differentiation and haemochorial placentation: mechanistic evidence in vivo and in vitro . Journal of Cell Science. 1991;99, part 4:681–692.
    1. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstetrics & Gynecology Annual. 1972;1:177–191.
    1. Whitley GSJ, Cartwright JE. Cellular and molecular regulation of spiral artery remodelling: lessons from the cardiovascular field. Placenta. 2010;31(6):465–474.
    1. Page EW. The relation between hydatid moles, relative ischaemia of the gravid uterus and the placental origin of eclampsia. American Journal of Obstetrics & Gynecology. 1939;37:291–293.
    1. Rauramo I, Forss M. Effect of exercise on placental blood flow in pregnancies complicated by hypertension, diabetes or intrahepatic cholestasis. Acta Obstetricia et Gynecologica Scandinavica. 1988;67(1):15–20.
    1. Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset PE. Placenta. 2009;30, supplement A:S43–S48.
    1. 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. British Journal of Obstetrics and Gynaecology. 1986;93(10):1049–1059.
    1. Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstetrics & Gynecology. 1992;80(2):283–285.
    1. Genbacev O, Zhou Y, Ludlow JW, Fisher SJ. Regulation of human placental development by oxygen tension. Science. 1997;277(5332):1669–1672.
    1. Albaiges G, Missfelder-Lobos H, Lees C, Parra M, Nicolaides KH. One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks’ gestation. Obstetrics & Gynecology. 2000;96(4):559–564.
    1. Lyall F, Belfort B. Pre-eclampsia Etiology and Clinical Practice. Cambridge, UK: Cambridge University Press, The Edinburgh Building; 2007.
    1. Fayyad AM, Harrington KF. Prediction and prevention of preeclampsia and IUGR. Early Human Development. 2005;81(11):865–876.
    1. Mütze S, Rudnik-Schöneborn S, Zerres K, Rath W. Genes and the preeclampsia syndrome. Journal of Perinatal Medicine. 2008;36(1):38–58.
    1. Marshall Graves JA. Genomic imprinting, development and disease—is pre-eclampsia caused by a maternally imprinted gene? Reproduction, Fertility and Development. 1998;10(1):23–29.
    1. Ros HS, Lichtenstein P, Lipworth L, Cnattingius S. Genetic effects on the liability of developing pre-eclampsia and gestational hypertension. American Journal of Medical Genetics. 2000;91(4):256–260.
    1. Haig D. Gestational drive and the green-bearded placenta. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(13):6547–6551.
    1. Roberts CT. IFPA award in placentology lecture: complicated interactions between genes and the environment in placentation, pregnancy outcome and long term health. Placenta. 2010;31:S47–S53.
    1. Dekker G, Robillard PY, Roberts C. The etiology of preeclampsia: the role of the father. Journal of Reproductive Immunology. 2011;89(2):126–132.
    1. Goddard KAB, Tromp G, Romero R, et al. Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes. Human Heredity. 2007;63(1):1–16.
    1. Trogstad L, Skrondal A, Stoltenberg C, Magnus P, Nesheim BI, Eskild A. Recurrence risk of preeclampsia in twin and singleton pregnancies. American Journal of Medical Genetics A. 2004;126(1):41–45.
    1. Carreiras M, Montagnani S, Layrisse Z. Preeclampsia: a multifactorial disease resulting from the interaction of the feto-maternal HLA genotype and HCMV infection. American Journal of Reproductive Immunology. 2002;48(3):176–183.
    1. Johnson MP, Roten LT, Dyer TD, et al. The ERAP2 gene is associated with preeclampsia in Australian and Norwegian populations. Human Genetics. 2009;126(5):655–666.
    1. Fenstad MH, Johnson MP, Roten LT, et al. Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q. PLoS ONE. 2010;5(9) Article ID e12993.
    1. Moreau P, Contu L, Alba F, et al. HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage. Biology of Reproduction. 2008;79(3):459–467.
    1. Srinivas SK, Morrison AC, Andrela CM, Elovitz MA. Allelic variations in angiogenic pathway genes are associated with preeclampsia. American Journal of Obstetrics & Gynecology. 2010;202(5):445.e1–445.e11.
    1. Shim JY, Jun JK, Jung BK, et al. Vascular endothelial growth factor gene +936 C/T polymorphism is associated with preeclampsia in Korean women. American Journal of Obstetrics & Gynecology. 2007;197(3):271.e1–271.e4.
    1. Williams PJ, Pipkin FB. The genetics of pre-eclampsia and other hypertensive disorders of pregnancy. Best Practice and Research: Clinical Obstetrics and Gynaecology. 2011;25(4):405–417.
    1. Escher G, Cristiano M, Causevic M, et al. High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome. Nephrology Dialysis Transplantation. 2009;24(6):1870–1875.
    1. Lim PO, Macdonald TM, Holloway C, et al. Variation at the aldosterone synthase (CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. Journal of Clinical Endocrinology and Metabolism. 2002;87(9):4398–4402.
    1. Seremak-Mrozikiewicz A, Drews K, Wender-Ozegowska E, Mrozikiewicz PM. The significance of genetic polymorphisms of factor v leiden and prothrombin in the preeclamptic polish women. Journal of Thrombosis and Thrombolysis. 2010;30(1):97–104.
    1. Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstetrics & Gynecology. 2005;105(1):182–192.
    1. Faisel F, Romppanen EL, Hiltunen M, et al. Susceptibility to pre-eclampsia in Finnish women is associated with R485K polymorphism in the factor V gene, not with Leiden mutation. European Journal of Human Genetics. 2004;12(3):187–191.
    1. Yamada N, Arinami T, Yamakawa-Kobayashi K, et al. The 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene is associated with severe preeclampsia. Journal of Human Genetics. 2000;45(3):138–141.
    1. Mtiraoui N, Zammiti W, Ghazouani L, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction. 2006;131(2):395–401.
    1. Sharma P, Senthilkumar RD, Brahmachari V, et al. Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies. Lipids in Health and Disease. 2006;5, article 1
    1. Gos M, Jr., Szpecht-Potocka A. Genetic basis of neural tube defects: II. Genes correlated with folate and methionine metabolism. Journal of Applied Genetics. 2002;43(4):511–524.
    1. Kluijtmans LAJ, Young IS, Boreham CA, et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood. 2003;101(7):2483–2488.
    1. Dasarathy J, Gruca LL, Bennett C, et al. Methionine metabolism in human pregnancy. American Journal of Clinical Nutrition. 2010;91(2):357–365.
    1. Bermúdez M, Briceño I, Gil F, Bernal J. Homocysteine and polymorphisms of cystathionine synthase and methylentetrahydrofolate reductase in a healthy population from Colombia. Colombia Medica. 2006;37(1):46–52.
    1. Vaughn JD, Bailey LB, Shelnutt KP, et al. Methionine synthase reductase 66A→G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C→T variant. Journal of Nutrition. 2004;134(11):2985–2990.
    1. Hague WM. Homocysteine and pregnancy. Best Practice and Research: Clinical Obstetrics and Gynaecology. 2003;17(3):459–469.
    1. Drennan CL, Huang S, Drummond JT, Matthews RG, Ludwig ML. How a protein binds B12: a 3.0 Å X-ray structure of B12-binding domains of methionine synthase. Science. 1994;266(5191):1669–1674.
    1. van der Put NMJ, Eskes TKAB, Blom HJ. Is the common 677C→T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. QJM. 1997;90(2):111–115.
    1. Furness DLF, Fenech MF, Khong YT, Romero R, Dekker GA. One-carbon metabolism enzyme polymorphisms and uteroplacental insufficiency. American Journal of Obstetrics & Gynecology. 2008;199(3):276.e1–276.e8.
    1. Georgiadou D, Hearn A, Evnouchidou I, et al. Placental leucine aminopeptidase efficiently generates mature antigenic peptides in vitro but in patterns distinct from endoplasmic reticulum aminopeptidase 1. Journal of Immunology. 2010;185(3):1584–1592.
    1. York IA, Brehm MA, Zendzian S, Towne CF, Rock KL. Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(24):9202–9207.
    1. Goto Y, Ogawa K, Hattori A, Tsujimoto M. Secretion of endoplasmic reticulum aminopeptidase 1 is involved in the activation of macrophages induced by lipopolysaccharide and interferon-γ . Journal of Biological Chemistry. 2011;286(24):21906–21914.
    1. Nagase T, Ishikawa KI, Miyajima N, et al. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro . DNA Research. 1998;5(1):31–39.
    1. Hill LD, Hilliard DD, York TP, et al. Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study. BMC Medical Genetics. 2011;12, article 64
    1. Langat DL, Wheaton DA, Platt JS, Sifers T, Hunt JS. Signaling pathways for B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in human placenta. The American Journal of Pathology. 2008;172(5):1303–1311.
    1. Phillips TA, Ni J, Hunt JS. Cell-specific expression of B lymphocyte (APRIL, BLyS)- and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas. Journal of Leukocyte Biology. 2003;74(1):81–87.
    1. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacological Reviews. 2004;56(4):549–580.
    1. Lyall F, Greer IA. The vascular endothelium in normal pregnancy and pre-eclampsia. Reviews of Reproduction. 1996;1(2):107–116.
    1. Zhou Y, McMaster M, Woo K, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. The American Journal of Pathology. 2002;160(4):1405–1423.
    1. Bányász I, Bokodi G, Vásárhelyi B, et al. Genetic polymorphisms for vascular endothelial growth factor in perinatal complications. European Cytokine Network. 2006;17(4):266–270.
    1. Garza-Veloz I, Castruita-De la Rosa C, Cortes-Flores R, et al. No association between polymorphisms/haplotypes of the vascular endothelial growth factor gene and preeclampsia. BMC Pregnancy and Childbirth. 2011;11, article 35
    1. Thuillez C, Richard V. Targeting endothelial dysfunction in hypertensive subjects. Journal of Human Hypertension. 2005;19, supplement 1:S21–S25.
    1. Serrano NC, Casas JP, Díaz LA, et al. Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study. Hypertension. 2004;44(5):702–707.
    1. Kobashi G, Yamada H, Ohta K, Kato E, Ebina Y, Fujimoto S. Endothelial nitric oxide synthase gene (NOS3) variant and hypertension in pregnancy. American Journal of Medical Genetics. 2001;103(3):241–244.
    1. Sewer MB, Waterman MR. ACTH modulation of transcription factors responsible for steroid hydroxylase gene expression in the adrenal cortex. Microscopy Research and Technique. 2003;61(3):300–307.
    1. Battinelli EM, Bauer KA. Thrombophilias in pregnancy. Hematology/Oncology Clinics of North America. 2011;25(2):323–333.
    1. Myatt L, Webster RP. Is vascular biology in preeclampsia better? Journal of Thrombosis and Haemostasis. 2009;7(3):375–384.
    1. Dudding T, Heron J, Thakkinstian A, et al. Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis. Journal of Thrombosis and Haemostasis. 2008;6(11):1869–1875.
    1. Costa LG, Giordano G, Furlong CE. Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: the hunt goes on. Biochemical Pharmacology. 2011;81(3):337–344.
    1. Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. Journal of Lipid Research. 2005;46(6):1239–1247.
    1. Kim YJ, Park H, Lee HY, et al. Paraoxonase gene polymorphism, serum lipid, and oxidized low-density lipoprotein in preeclampsia. European Journal of Obstetrics Gynecology and Reproductive Biology. 2007;133(1):47–52.
    1. Uzun H, Benian A, Madazli R, Topçuoğlu MA, Aydin S, Albayrak M. Circulating oxidized low-density lipoprotein and paraoxonase activity in preeclampsia. Gynecologic and Obstetric Investigation. 2005;60(4):195–200.
    1. Lawlor DA, Gaunt TR, Hinks LJ, et al. The association of the PON1 Q192R polymorphism with complications and outcomes of pregnancy: findings from the British Women’s Heart and Health cohort study. Paediatric and Perinatal Epidemiology. 2006;20(3):244–250.
    1. Isbilen E, Yilmaz H, Arzu Ergen H, Unlucerci Y, Isbir T, Gurdol F. Association of paraoxonase 55 and 192 gene polymorphisms on serum homocysteine concentrations in preeclampsia. Folia Biologica. 2009;55(2):35–40.
    1. Acilmis YG, Dikensoy E, Kutlar AI, et al. Homocysteine, folic acid and vitamin B12 levels in maternal and umbilical cord plasma and homocysteine levels in placenta in pregnant women with pre-eclampsia. Journal of Obstetrics and Gynaecology Research. 2011;37(1):45–50.

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