Copyright © 2004 by the European Society of Cardiology.
Letter to the Editor
Functional implications of polymorphisms of endothelial nitric oxide synthase gene: Reply
a Deutsches Herzzentrum München and 1. Medizinische Klinik rechts der Isar, Technische Universität München, München, Germany
b Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, and Institut für Humangenetik, GSF Forschungszentrum, Neuherberg, Germany
* Correspondence to: W. Koch, Deutsches Herzzentrum München and 1. Medizinische Klinik rechts der Isar, Technische Universität München, Lazarettstrasse 36, 80636 München, Germany. Tel: +49-89-1218-2601; fax: +49-89-1218-3053
E-mail address: wkoch{at}dhm.mhn.de
We appreciate the interest of Nagassaki and colleagues in our study.1The main finding of this study was that the 894 G/T polymorphism of the endothelial nitric oxide synthase (eNOS) gene correlates with the risk for death and myocardial infarction after coronary artery stenting.1We underscored in the Discussion section that it is presently not possible to outline a causal relationship between the 894 G/T polymorphism and the outcome after stenting.1We discussed the possible functional role of the 894 G/T polymorphism in the light of previously reported findings relative to the susceptibility to proteolytic cleavage of eNOS with asp298 (expressed in T allele carriers).2Nagassaki and colleagues refer to another study which findings did not support increased cleavage in T allele carriers3and propose another explanation for the association found in our study. They hypothesize that behind the association between the 894 G/T polymorphism and the clinical outcome after stenting stays another polymorphism, the –786 T/C polymorphism in the promoter region of the eNOS gene. The authors of the letter to the editor find the basis for their hypothesis in a report suggesting that the –786 C allele is associated with reduced eNOS gene expression4and in the linkage disequilibrium between the 894 T and –786 C alleles described in one of their own studies.5We genotyped the same population included in our previous study1for the –786 T/C polymorphism: 37.4% were of the –786 TT genotype, 47.5% of the –786 TC genotype, and 15.2% of the –786 CC genotype. The estimated linkage disequilibrium D' between the 894 T and –786 C alleles was 0.49. In our population, the combined 1-year incidence of death and myocardial infarction was 5.7% among –786 CC patients as compared to 3.8% among the –786 T allele carriers (P=0.15). Taken together, all these findings show that we are still unable to offer a definite mechanism underlying the association between the 894 G/T polymorphism and the outcome of patients undergoing coronary artery stenting.
References
- Gorchakova O, Koch W, von Beckerath N et al. Association of a genetic variant of endothelial nitric oxide synthase with the 1 year clinical outcome after coronary stent placement. Eur Heart J. 2003;24:820–827.
[Abstract/Free Full Text] - Tesauro M, Thompson WC, Rogliani P et al. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA. 2000;97:2832–2835.
[Abstract/Free Full Text] - Fairchild TA, Fulton D, Fontana JT et al. Acidic hydrolysis as a mechanism for the cleavage of the Glu298
Asp variant of human endothelial nitric-oxide synthase. J Biol Chem. 2001;276:26674–26679.[Abstract/Free Full Text] - Nakayama M, Yasue H, Yoshimura M et al. –786TC mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation. 1999;99:2864–2870.
[Abstract/Free Full Text] - Tanus-Santos JE, Desai M, Flockhart DA. Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics. 2001;11:719–725.[CrossRef][Web of Science][Medline]
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