Effect of the angiotensin‐converting enzyme gene deletion polymorphism on the risk of venous thromboembolism

Abstract

Summary. Allele frequencies for the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene were determined in a large case±control study of 517 unselected patients with venous thromboembolism and 478 blood donors. The D allele frequency was 0´53 [95% confidence interval (CI) 0´50±0´56] in patients and 0´54 (95% CI 0´50±0´57) in controls, giving an odds ratio for the D allele of 0´97 (95% CI 0´81±1´16). In the same population, the odds ratio for the factor V Leiden mutation (F5G1691A) was 6´9 (95% CI 4´0±11´9). Therefore, the ACE I/D polymorphism is not a risk factor in a representative group of unselected patients with venous thromboembolism. The possibility that the I/D polymorphism is a risk factor for venous thromboembolism specifically after hip replacement cannot be excluded.Keywords: thrombosis, angiotensin-converting enzyme, ACE, factor V Leiden.Human angiotensin-converting enzyme (ACE) is a dipeptidyl carboxypeptidase present at high concentrations on the luminal surfaces of capillary endothelial cells. It is also present in the kidney, brain and liver and is present at lower concentrations in plasma. ACE cleaves the carboxy-terminal dipeptide of angiotensin I, releasing the physiologically active octapeptide angiotensin II. This potently vasoconstrictive molecule plays a key role in modulating vascular tone. In addition, ACE degrades the vasodilator bradykinin, producing a synergistic effect with angiotensin II (Dzau, 1994). The ACE gene contains a polymorphism which results in the insertion (I) or deletion (D) of a 287-bp fragment of intron 16, producing three genotypes, DD and II homozygotes and ID heterozygotes. The I allele has a sequence similar to a silencer sequence, which may explain why the D allele is associated with higher ACE levels than the I allele. The DD and ID genotypes are associated with ACE levels 1´7 and 1´3 times greater than those observed in subjects with the II genotype. This polymorphism accounts for 47% of the serum ACE level variance (Rigat et al, 1990).

Maternal-Fetal Flow, Negative Events, and Preeclampsia

“…14 Moreover, it has been assumed that the I allele has a sequence similar to a silencer sequence, which might explain why the D allele is associated with higher ACE levels than the I allele. 15 ACE activity and ACE I/D polymorphism were not found to be associated with PE in previous studies, 9,16,17 but no information is available about the effect of this polymorphism on maternal-fetal hemodynamics in women at high risk of PE.…”

The Presence of PAI-1 4G/5G and ACE DD Genotypes Increases the Risk of Early-Stage AVF Thrombosis in Hemodialysis Patients

“…Thus, it was thought that the ACE I/D gene polymorphism was not a risk factor in patients with thromboembolism. 26 In another study, Isbir et al determined a relationship between arteriovenous graft (AVG) thrombosis and ACE I/D genotype. They found higher risks in the ID genotype when compared with II and DD genotypes.…”

Lack of association between potential prothrombotic genetic risk factors and arterial and venous thrombosis

“…Prandoni's study (2007) of patients with venous thrombosis showed a moderate increase in risk for male patients with the DD genotype, but no increase in risk for women patients with the same genotype. Jackson et al (2000) in another case-control study of 500 unselected patients showed that the ID polymorphism in the ACE gene was not a risk factor for venous thromboembolism. Lopaciuk et al (2010) analyzed the genetic profiles of 38 patients who had a postoperative symptomatic pulmonary embolism or proximal deep venous thrombosis after arthroplasty, and 241 control subjects without thrombosis.…”

“…Two of its most common polymorphisms are -401 G/T and -402 G/A. These polymorphisms of the promoter region of the FVII gene are associated with changes in FVII blood levels, and represent important risk factors for quantitative cardiovascular diseases, including ischemic heart disease and arterial or venous thrombosis (Jackson et al, 2000;Eroğlu et al, 2010Eroğlu et al, , 2011.…”

“…The plasma levels of this enzyme in humans are related to the insertion/deletion (I/D) polymorphism in the ACE gene. The deletion of a 287-bp sequence in intron 16 of the ACE gene is associated with increased levels of transcription of messenger RNA and hence with increased ACE expression (Jackson et al, 2000;Fatini et al, 2009). Thus, carriers of the DD genotype are associated with higher plasma levels of the enzyme than those with the ID (intermediate levels) or II (low levels) genotypes (Jackson et al, 2000;Zhang et al, 2012).…”