Thromb Haemost 2003; 89(05): 847-852
DOI: 10.1055/s-0037-1613472
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The deletion polymorphism in the angiotensin-converting enzyme gene is a moderate risk factor for venous thromboembolism

Mario von Depka
1   Department of Haematology/Oncology, Hannover Medical School, Hanover, Germany
,
Andreas Czwalinna
1   Department of Haematology/Oncology, Hannover Medical School, Hanover, Germany
,
Cornelia Wermes
1   Department of Haematology/Oncology, Hannover Medical School, Hanover, Germany
,
Roswith Eisert
1   Department of Haematology/Oncology, Hannover Medical School, Hanover, Germany
,
Inge Scharrer
2   Centre of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
,
Arnold Ganser
1   Department of Haematology/Oncology, Hannover Medical School, Hanover, Germany
,
Silke Ehrenforth
2   Centre of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
› Institutsangaben
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Publikationsverlauf

Received after 04. September 2002

Accepted after revision 27. Februar 2003

Publikationsdatum:
09. Dezember 2017 (online)

Summary

ACE displays potent vasoconstrictive effects, attenuation of fibrinolysis, and platelet activation and aggregation, thus possibly promoting venous thromboembolism (VTE). The ACE gene contains an insertion (I) or deletion (D) polymorphism accounting for 50% of the variation in serum ACE concentration. To evaluate the role of the I/D polymorphism in VTE, its prevalence was determined in 931 patients with VTE and 432 blood donors. The prevalence of the DD genotype was 27.6% in patients and 21.3% in controls (OR 1.4; p <0.02). In multivariate analysis there was a trend of the DD genotype to be an independent risk factor (OR 1.4; p = 0.08). No differences in DD genotype prevalence according to exogenous risk factors were found. Coinheritance of FV G1691A, PT G20210A mutation, and PS deficiency with the DD genotype increased the relative risk of VTE. Thus, the ACE DD genotype is a moderate risk factor of hereditary thrombophilia. Exogenous risk factors did not alter the manifestation of VTE among carriers of the DD genotype, whereas coinheritance of the DD genotype with the aforementioned defects increased the risk for VTE considerably.

 
  • References

  • 1 Hubert C, Houot AM, Corvol P, Soubrier F.. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem 1991; 266: 15377-83.
  • 2 Rigat N, Hubert C, Alhenc-Gelas F, Cambien F, Cor N.. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343-6.
  • 3 Cambien F.. The angiotensin-converting enzyme (ACE) genetic polymorphism: its relationship with plasma ACE level and myocardial infarction. Clin Genet 1994; 46: 94-101.
  • 4 Cody RJ.. The integrated effects of angiotensin II. Am J Cardiol 1997; 79: 9-11.
  • 5 Seligsohn U, Zivelin A.. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297-301.
  • 6 Vaughan DE.. Endothelial function, fibrinolysis, and angiotensin-converting enzyme inhibition. Clin Cardiol 1997; 20: II-34-7.
  • 7 Vaughan DE.. The renin-angiotensin system and fibrinolysis. Am J Cardiol 1997; 79: 12-6.
  • 8 Larsson PT, Schwieler JH, Wallen NH, Hjemdahl P.. Acute effects of angiotensin II on fibrinolysis in healthy volunteers. Blood Coag Fibrinolysis 1999; 10: 19-24.
  • 9 Rakugi H, Kim DK, Krieger JE, Wang DS, Dzau VJ.. Induction of angiotensin converting enzyme in the neointima after vascular injury: possible role in restenosis. J Clin Invest 1994; 93: 339-46.
  • 10 Cambien F, Poirier O, Lecerf L.. et al. Deletion po1ymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641-4.
  • 11 Van Bockxmeer FM, Mamotte CDS, Burkes V, Taylor RR.. Angiotensin-converting enzyme gene polymorphism and premature coronary heart disease. Clin Sci 2000; 99: 247-51.
  • 12 Keavney B, McKenzie C, Parish S, Palmer A, Clark S, Youngman L, Delepine M, Lathrop M, Peto R, Collins R.. Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. Lancet 2000; 355: 434-42.
  • 13 Philipp CS, Dilley A, Saidi P, Evatt B, Austin H, Zawadsky J, Harwood D, Ellingsen D, Barnhart E, Phillips DJ, Hooper WC.. Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Haemost 1998; 80: 869-73.
  • 14 Gonzalez Ordonez AJ, Femandez Carreira JM, Medina Rodriguez JM.. et al. Risk of venous thromboembolism associated with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene. Blood Coagul Fibrinolysis 2000; 11: 485-90.
  • 15 Dahlbäck B.. Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene. Haemostasis 1994; 24: 139-51.
  • 16 Bertina RM, Koeleman BP, Koster T.. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
  • 17 Poort SR, Rosendaal FR, Reitsma PR, 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.
  • 18 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C.. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-3.
  • 19 Comp PC, Nixon RR, Cooper MR, Esmon CT.. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8.
  • 20 Egeberg O.. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-30.
  • 21 Rigat N, Hubert C, Corvol P, Soubrier F.. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP 1). Nucleic Acids Res 1992; 20: 1433.
  • 22 Shanmuan V, Sell KW, Saha BK.. Mistyping ACE heterozygotes. PCR Methods Appl 1993; 3: 120-1.
  • 23 von Depka M, Nowak-Gottl U, Eisert R.. et al. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000; 96: 3364-8.
  • 24 Dilley A, Austin H, Hooper WC, Lally C, Ribeiro MJ, Wenger NK, Silva V, Rawlins P, Evatt B.. Relation of three genetic traits to venous thrombosis in an African-American population. Am J Epidemiol 1998; 147: 30-5.
  • 25 Jackson A, Brown K, Langdown J, Luddington R, Baglin T.. Effect of the angiotensin-converting enzyme gene deletion po1ymorphism on the risk of venous thromboembolism. Br J Haematol 2000; 111: 562-4.
  • 26 Poikolainen E, Hendolin H.. Effects of lumbar epidural analgesia and general anaesthesia on flow velocity in the femoral vein and postoperative deep vein thrombosis. Acta Chir Scand 1983; 149: 361-4.
  • 27 Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE.. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II: evidence of a potential interaction between the reninangiotensin system and fibrinolytic function. Circulation 1993; 87: 1969-73.
  • 28 Vaughan DE, Lazos SA, Tong K.. Angiotensin II regulates the expression of plasminogen activator inhibitor-l in cultured endothelial cells: a potential link between the reninangiotensin system and thrombosis. J Clin Invest 1995; 95: 995-1001.
  • 29 Kerins DM, Hao Q, Vaughan DE.. Angiotensin induction of PAI-l expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995; 96: 2515-20.
  • 30 Kim DK, Kim JW, Kim S.. et al. Polymorphism of Angiotensin Converting Enzyme Gene Is Associated With Circulating Levels of Plasminogen Activator Inhibitor-I. Arterioscler Thromb Vasc Biol 1997; 17: 3242-7.
  • 31 Meade TW, Ruddoek V, Stirling Y, Chakrabarti R, Miller GJ... Fibrinolytic activity, clotting factors and long-term incidence of ischaemie heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
  • 32 Ridker PM, Hennekens CH, Stampfer MJ, Manson J, Vaughan DE.. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-3.
  • 33 Bauer KA.. Conventional fibrinolytic assays for the evaluation of patients with venous thrombosis: don’t bother [Editorial]. Thromb Haemost 2001; 85: 377-8.
  • 34 Moore JH, Smolkin ME, Lamb JM, Brown NJ, Vaughan DE.. The relationship between plasma t-PA and PAI-1 levels is dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. Clin Genet 2002; 62: 53-9.