Prothrombotic Genotypes Are not Associated with Pre-eclampsia and Gestational Hypertension: Results from a Large Population-based Study and Systematic Review

E. R. Morrison; Z. H. Miedzybrodzka; D. M. Campbell; N. E. Haites; B. J. Wilson; M. S. Watson; M. Greaves; M. A. Vickers

doi:10.1055/s-0037-1613083

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 87(05): 779-785
DOI: 10.1055/s-0037-1613083

In Focus

Schattauer GmbH

Prothrombotic Genotypes Are not Associated with Pre-eclampsia and Gestational Hypertension: Results from a Large Population-based Study and Systematic Review

E. R. Morrison

¹Departments of Medicine and Therapeutics, University of Aberdeen, Scotland

,

Z. H. Miedzybrodzka

¹Departments of Medicine and Therapeutics, University of Aberdeen, Scotland

²Molecular and Cell Biology, University of Aberdeen, Scotland

,

D. M. Campbell

³Department of Obstetrics and Gynaecology, University of Aberdeen, Scotland

,

N. E. Haites

¹Departments of Medicine and Therapeutics, University of Aberdeen, Scotland

²Molecular and Cell Biology, University of Aberdeen, Scotland

,

B. J. Wilson

⁴Department of Public Health, University of Aberdeen, Scotland

,

M. S. Watson

⁴Department of Public Health, University of Aberdeen, Scotland

,

M. Greaves

¹Departments of Medicine and Therapeutics, University of Aberdeen, Scotland

,

M. A. Vickers

¹Departments of Medicine and Therapeutics, University of Aberdeen, Scotland

› Institutsangaben

Abstract

Summary

DNA samples collected as part of a large population-based casecontrol study were genotyped to examine the associations of five prothrombotic gene polymorphisms with pre-eclampsia (PE) and gestational hypertension (GH). The polymorphisms studied were: G1691A in Factor V (Factor V Leiden; FVL), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, plasminogen activator inhibitor-1 4G/5G and the platelet collagen receptor α₂β₁ C807T. A group of 404 women who developed PE were retrospectively compared with 303 women with GH and 164 control women. The frequency of genotypes did not differ significantly between cases of PE or GH and controls for any of the five polymorphisms studied. We conclude that these prothrombotic genotypes are not associated with the development of PE or GH in our population. The systematic review supports our conclusion, for all but cases of severe disease, which appear to be associated with FVL and, to a lesser extent, MTHFR C677T. There is little value in antenatal screening for prothrombotic polymorphisms to predict the development of pre-eclampsia or gestational hypertension.

Keywords

Pre-eclampsia - gestational hypertension - prothrombotic polymorphisms - Factor V Leiden - MTHFR

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Referenzen

References
1 Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet 2001; 357: 53-6.
2 Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998; 179: 1359-75.
3 Hayman R, Brockelsby J, Kenny L, Baker P. Preeclampsia: the endothelium, circulating factor(s) and vascular endothelial growth factor. J Soc Gynecol Investig 1999; 06: 3-10.
4 VanWijk MJ, Kublickiene K, Boer K, VanBavel E. Vascular function in preeclampsia. Cardiovasc Res 2000; 47: 38-48.
5 Chesley LC, Cooper DW. Genetics of hypertension in pregnancy: possible single gene control of pre-eclampsia and eclampsia in the descendents of eclamptic women. Br J Obstet Gynaecol 1986; 93: 898-908.
6 Arngrimsson R, Bjornsson S, Geirsson RT, Bjornsson H, Walker JJ, Snaedal G. Genetic and familial predisposition to eclampsia and preeclampsia in a defined population. Br J Obstet Gynaecol 1990; 97: 762-9.
7 Arngrimsson R, Bjornsson S, Geirsson RT. Analysis of different inheritance patterns in pre-eclampsia/eclampsia syndrome. Hypertens Preg 1995; 14: 27-38.
8 Cincotta RB, Brennecke SP. Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas. Int J Gynecol Obstet 1998; 60: 23-7.
9 Mogren I, Hogberg U, Winkvist A, Stenlund H. Familial occurrence of preeclampsia. Epidemiology 1999; 10: 518-22.
10 Treloar SA, Cooper DW, Brennecke SP, Grehan MM, Martin NG. An Australian twin study of the genetic basis of preeclampsia and eclampsia. Am J Obstet Gynecol 2001; 184: 374-81.
11 Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, Varner MW. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001; 344: 867-72.
12 Perry Jr KG, Martin Jr JN. Abnormal hemostasis and coagulopathy in preeclampsia and eclampsia. Clin Obstet Gynecol 1992; 35: 338-50.
13 Bellart J, Gilabert R, Angles A, Piera V, Miralles RM, Monasterio J, Cabero L. Tissue factor levels and high ratio of fibrinopeptide A:D-dimer as a measure of endothelial procoagulant disorder in pre-eclampsia. Br J Obstet Gynaecol 1999; 106: 594-7.
14 Murphy RP, Donoghue C, Nallen RJ, D’Mello M, Regan C, Whitehead AS, Fitzgerald DJ. Prospective evaluation of the risk conferred by factor V Leiden and the thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 2000; 20: 266-70.
15 van Pampus MG, Dekker GA, Wolf H, Huijgens PC, Koopman MMW, von Blomberg ME, Buller HR. High prevalence of haemostatic abnormalities in women with a history of severe pre-eclampsia. Am J Obstet Gynecol 1999; 180: 1146-50.
16 Kupferminc MJ, Eldor A. Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing J. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
17 Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe pre-eclampsia and high frequency genetic thrombophilic mutations. Obstet Gynecol 2000; 96: 45-9.
18 Nagy B, Toth T, Rigo Jr J, Karadi I, Romics L, Papp Z. Detection of Factor V mutation in severe pre-eclamptic Hungarian women. Clin Genet 1998; 53: 478-81.
19 Grandone E, Margaglione M, Colaizzo D, Cappucci G, Paladini D, Martinelli P, Montanaro S, Pavone G, Di Minno G. Factor V Leiden, C→T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997; 77: 1052-4.
20 Grandone E, Margaglione M, Colaizzo D, Cappucci G, Scianname N, Montanaro S, Paladini D, Martinelli P, Di Minno G. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999; 81: 349-52.
21 Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Pre-eclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176: 457-60.
22 von Tempelhoff GF, Heilmann L, Spanuth E, Kunzmann E, Hommel G. Incidence of the factor V Leiden mutation, coagulation inhibitor deficiency, and elevated antiphospholipid antibodies in patients with pre-eclampsia or HELLP-syndrome. Thromb Res 2000; 100: 363-5.
23 Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM. Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia. Am J Obstet Gynecol 2001; 185: 153-7.
24 Mimuro S, Lahoud R, Beutler L, Trudinger B. Changes in resistance to activated protein C in the course of pregnancy and prevalence of factor V mutation. Aust N Z J Obstet Gynaecol 1998; 38: 200-4.
25 Powers RW, Minich LA, Lykins DL, Ness RB, Crombleholme WR, Roberts JM. Methylenetetrahydrofolate reductase polymorphism, folate and susceptibility to pre-eclampsia. J Soc Gynecol Investig 1999; 06: 74-9.
26 Kaiser T, Brennecke SP, Moses EK. C677T methylenetetrahydrofolate reductase polymorphism is not a risk factor for pre-eclampsia/eclampsia among Australian women. Hum Hered 2001; 51: 20-2.
27 Kobashi G, Yamada H, Asano T, Nagano S, Hata A, Kishi R, Fujimoto S, Kondo R. Absence of association between a common mutation in the MTHFR gene and preeclampsia in Japanese women. Am J Med Genet 2000; 93: 122-5.
28 Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T. Methylenetetrahydrofolate reductase polymorphism and preeclampsia. J Med Genet 1997; 34: 525-6.
29 Kupferminc MJ, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and 2nd trimester loss. Acta Obstet Gynecol Scand 2000; 79: 963-7.
30 O’Shaughnessy KM, Fu B, Ferraro F, Lewis I, Downing S, Morris NH. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort. Hypertension 1999; 33: 1338-41.
31 De Groot CJM, Bloemenkamp KWM, Duvekot EJ, Helmerhorst FM, Bertina RM, Van Der Meer F, De Ronde H, Oei SG, Kanhai HHH, Rosendaal FR. Preeclampsia and genetic risk factors for thrombosis: a casecontrol study. Am J Obstet Gynecol 1999; 181: 975-80.
32 Rigo Jr J, Nagy B, Fintor L, Tanyi J, Beke A, Karadi I, Papp Z. Maternal and neonatal outcome of pre-eclamptic pregnancies: the potential roles of factor V Leiden mutation and 5,10 MTHFR. Hypertens Preg 2000; 19: 163-72.
33 Dizon-Townson DS, Nelson LM, Easton K, Ward K. The Factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996; 175: 902-5.
34 Kim YJ, Williamson RA, Murray JC, Andrews J, Pietscher JJ, Peraud PJ, Merrill DC. Genetic susceptibility to pre-eclampsia: roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-basepair insertion at nucleotide 844 of the gene for cystathione β-synthase, and factor V Leiden mutation. Am J Obstet Gynecol 2001; 184: 1211-7.
35 Zusterzeel PLM, Visser W, Blom HJ, Peters WHM, Heil SG, Steegers EAP. Methylenetetrahydrofolate reductase polymorphisms in pre-eclampsia and the HELLP syndrome. Hypertens Preg 2000; 19: 299-307.
36 Lachmeijer AMA, Arngrimsson R, Bastiaans EJ, Pals G, ten Kate LP, de Vries JIP, Kostense PJ, Aarnoudse JG, Dekker GA. Mutations in the gene for MTHFR, homocysteine levels, and vitamin status in women with a history of PE. Am J Obstet Gynecol 2001; 184: 394-402.
37 Laivuori H, Kaaja R, Ylikorkala O, Hiltunen T, Kontula K. 677C→T polymorphism of the MTHFR gene and pre-eclampsia. Obstet Gynecol 2000; 96: 277-80.
38 Kaiser T, Brennecke SP, Moses EK. Methylenetetrahydrofolate reductase polymorphisms are not a risk factor for pre-eclampsia/eclampsia in Australian women. Gynecol Obstet Invest 2000; 50: 100-2.
39 Higgins JR, Kaiser T, Moses EK, North R, Brennecke SP. Prothrombin G20210A mutation: is it associated with pre-eclampsia?. Gynecol Obstet Invest 2000; 50: 254-752.
40 Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM, Hannaford P, Smith WCS. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life (submitted).
41 Samphier M, Thompson B. The Aberdeen Maternity and Neonatal databank. In: Prospective Longitudinal Records. Mednick SA, Baert AE. eds. Oxford University press; 1981
42 Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158: 892-98.
43 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
44 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
45 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluitmans LAJ, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
46 Falk G, Svensson H, Almquist A, Wiman B. Allele specific PCR for detection of a sequence polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene. Fibrinogen 1994; 08 (Suppl. 01) 45.
47 Di Paola J, Federici AB, Mannucci PM, Canciani MT, Kritzik M, Kunicki TJ, Nugent D. Low platelet α₂β₁ levels in Type 1 vWD correlate with impaired platelet function in a high shear stress system. Blood 1999; 93: 3578-82.
48 Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-86.
49 Bowen DJ, Bowley S, John M, Collins PW. Factor V Leiden (G1691A), the prothrombin 3’-untranslated region variant (G20210A) and thermolabile methylenetetrahydrofolate reductase (C677T): a single genetic test genotypes all three loci-determination of frequencies in the S. Wales population of the UK. Thromb Haemost 1998; 79: 949-54.
50 Botto LD, Yang Q. 5-10-methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 2000; 151: 862-77.
51 Mansfield MW, Stickland MH, Grant PJ. PAI-1 concentrations in firstdegree relatives of patients with non-insulin-dependent diabetes: metabolic and genetic associations. Thromb Haemost 1997; 77: 357-61.
52 Croft SA, Hampton KK, Sorrell JA, Steeds Rp, Channer KS, Samani NJ, Daly ME. The Gp1a C807T dimorphism associated with collagen receptor density is not a risk factor for myocardial infarction. Br J Haematol 1999; 106: 771-6.
53 Grandone E, Margaglione M, Colaizzo D, d’Addedda M, Cappucci G, Vecchione G, Scianname N, Pavone G, Di Minno G. Factor V Leiden is associated with repeated and recurrent unexplained foetal loss. Thromb Haemost 1997; 77: 822-4.
54 Mello G, Parretti E, Martini E, Mecacci F, La Torre P, Cioni R, Lucchetti R, Fedi S, Gori AM, Pepe G, Prisco D, Abbate R. Usefulness of screening for congenital or acquired hemostatic abnormalities in women with previous uncomplicated pregnancies. Haemostasis 1999; 29: 197-203.
55 Kobashi G, Yamada H, Asano T, Nagano S, Hata A, Kishi R, Kondo K, Fujimoto S. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan. Semin Thromb Hemost 1999; 25: 487-9.
56 Tuohy J. Multiple obstetric complications of factor V Leiden mutation. Aust N Z J Obstet Gynaecol 2000; 40: 203-4.
57 Krauss T, Augustin HG, Osmers R, Meden H, Unterhalt HM, Kuhn W. Activated protein C resistance and factor V Leiden in patients with HELLP syndrome. Obstet Gynecol 1998; 92: 457-60.
58 Nagy B, Rigo J, Toth T, Karadi I, Romics L, Papp Z. MTHFR polymorphism in healthy pregnant and pre-eclamptic women. Clin Chem 1998; 44: A15.
59 Chikosi AB, Moodley J, Pegoraro RJ, Lanning PA, Rom L. 5’,10 methylenetetrahydrofolate reductase polymorphism in black South African women with pre-eclampsia. Br J Obstet Gynaecol 1999; 106: 1219-20.
60 Rajkovic A, Mahomed K, Rozen R, Malinow MR, King IB, Williams MA. Methylenetetrahydrofolate reductase 677 C→T polymorphism, plasma folate, vitamin B(12) concentrations, and risk of preeclampsia among black African women from Zimbabwe. Mol Genet Metab 2000; 69: 33-9.
61 Yamada N, Arinami T, Yamakawa-Kobayashi K, Watanabe H, Sohda S, Hamada H, Kubo T, Hamaguchi H. The 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene is associated with severe preeclampsia. J Hum Genet 2000; 45: 138-41.
62 Glueck CJ, Phillips H, Cameron D, Wang P, Fontaine RN, Moore SK, Sieve-Smith L, Tracy T. 4G/5G polymorphism of the hypofibrinolytic plasminogen activator inhibitor Type 1 gene: an independent risk factor for serious pregnancy complications. Metabolism 2000; 49: 845-52.
63 Glueck CJ, Kupferminc MJ, Fontaine RN, Wang P, Weksler BB, Eldor A. Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol 2001; 97: 44-8.