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Interactive effects of the ACE DD polymorphism with the NOS III homozygous G849T (Glu298Asp) variant in determining endothelial function in coronary artery disease

Section of Vascular Medicine, Division of Cardiology, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Anjan K Chakrabarti

Section of Vascular Medicine, Division of Cardiology, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Chris Kehrer

Section of Vascular Medicine, Division of Cardiology, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Dana Pfeninnger

Section of Vascular Medicine, Division of Cardiology, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Robert D Brook

Section of Vascular Medicine, Division of Cardiology, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Niko Kaciroti

Department of Medicine, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Claire Duvernoy

Section of Vascular Medicine, Division of Cardiology, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Anthony A Killeen

Department of Medicine, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA

Sanjay Rajagopalan

Section of Vascular Medicine, Division of Cardiology, Clinical Pathology and Centre for Human Growth and Development, University of Michigan School of Medicine, Ann Arbor, MI, USA, srajagop{at}umich.edu

The products of nitric oxide synthase (NOS) and angiotensin-converting enzyme (ACE) play a critical role in determining vessel wall structure and function. Polymorphisms in both genes have been independently demonstrated to influence propensity to cardiovascular events. The purpose of this study was to determine the influence of the homozygous G849T(Glu298 Asp) polymorphism in NOS III on peripheral conduit artery endothelial function and to elucidate the modifier role, if any, of a common ACE polymorphism.

Three hundred and ninety-seven consecutive subjects presenting to the cardiac catheterization laboratory of the University of Michigan over a period of 18 months were recruited. DNA was extracted and polymerase chain reaction (PCR) analysis for ACE and NOS polymorphisms performed. Patients with homozygosity for G849T at both loci (TT) who belong to DD and II ACE genotype (groups 1 and 2) and those who are negative for this polymorphism (GG) and belong to either DD or II genotype (groups 3 and 4) were identified. The four groups then underwent determination of conduit endothelial function. Heterozygosity of Glu298-Asp or the ID variant of the ACE were not studied.

Median FMD value in the TT-DD group was 0.20 (-3.17, 2.01) compared with 2.23% (-0.29, 4.17) in the GG-II group. Median values in the TT-II and the GG-DD groups were 3.04 (-1.16, 6.61) and 2.46% (-1.83, 6.52) respectively. These values were not statistically significant (p > 0.05 by one-way ANOVA). Median nitroglycerin-mediated dilation in the four groups did not differ between the four groups (p = NS by ANOVA). Atherosclerosis burdens as assessed by angiography were not different across the groups.

In conclusion, the homozygous NOS III variant (GG) status does not seem to interact additively with the ACE homozygous DD genotype in determining flow-mediated vasodilation in individuals with established atherosclerosis and pre-existent endothelial dysfunction.

Key Words: ACE • coronary artery disease • endothelium • nitric oxide synthase • polymorphism

Vascular Medicine, Vol. 8, No. 3, 177-183 (2003)
DOI: 10.1191/1358863x03vm486oa


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