CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Gian Paolo Rossi, MD, FACC, FAHA* and
Maurizio Cesari, MD
* DMCS–Internal Medicine 4, University Hospital, via Giustiniani, 2, 35126 Padova, Italy (Email: gianpaolo.rossi{at}unipd.it).
To explain our (1) intriguing results on the effects of the T-786C (in the promoter) and the G894T (in exon 7) single nucleotide polymorphisms (SNP) of the endothelial nitric oxide (NO) synthase (eNOS) gene on cardiovascular mortality, Tanus-Santos et al. recalled that the former SNP alters the gene responsiveness to statins: statins would up-regulate eNOS expression (2) more potently in -786C homozygous (3) and therefore, these subjects would generate more NO while on statins than subjects with the other genotypes. Accordingly, atorvastatin increased NO availability and reduced inflammatory marker concentrations in CC, but not in TT healthy men (4). However, we found no significant interaction between statin treatment and the T-786C SNP affecting cardiovascular mortality (1). Moreover, only a minority of our patients were on statins (5); therefore, this mechanistic explanation is unlikely.
As with Tanus-Santos et al., we also found that the T-786C SNP did not affect nitrite/nitrate levels; however, functional data (6) indicate that the T-786C SNP affects NO bioactivity by altering the gene responsiveness to shear stress (7). Thus, the "Janus" nature of eNOS might reveal itself under conditions of oxidant stress, leading to decreased plaque stability and cardiovascular events (1).
Antoniades et al. raised another appealing hypothesis: an interaction of the 786T with the 894T allele constituting the 894T/786T haplotype might lower eNOS expression and increase susceptibility of eNOS to proteolytic cleavage, resulting into transiently increased oxidant stress and inflammatory status during acute conditions (8). However, the G894T SNP lies within a loop on the external surface of eNOS and does not make contact with either the active site of the enzyme, or the dymerization interface, suggesting that, if functional, this SNP could act by a mechanism independent of eNOS catalysis. Moreover, the increased susceptibility to cleavage of the Asp298-encoded eNOS enzyme has been shown to be artifactual (reviewed by Casas et al.) (9). Therefore, whether the 894T allele bears functional consequences remains controversial. Nonetheless, the linkage disequilibrium of the T-786C and G894T SNP (1) can explain the association of the latter SNP with coronary heart disease (CHD), as we pointed out.
Antoniades et al. stated that an increased risk of CHD (odds ratio [OR] = 1.31) for the 894T allele carriers was reported; however, the excess risk deriving from meta-analysis of cross-sectional association studies, which are prone to stratification biases, should be viewed cautiously. In fact, a much larger meta-analysis led to a markedly reduced estimate of risk (OR = 1.17) (9).
Consistent with prospective study results in high-risk patients (1,10), we found no evidence for a prognostic effect of the 894T allele. Thus, even if the 894T homozygosity would imply a blunted NO production and/or higher levels of oxidized low-density lipoprotein and proinflammatory cytokines during acute coronary events, overall prospective cohort studies show no prognostic effect in high-risk patients.
Finally, although underlying the fact that intriguing results such as ours are crucial for generating novel hypotheses, we agree that the elucidation of the complex interplay between the eNOS gene haplotypes and environmental factors deserves further research.
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1. Rossi GP, Maiolino G, Zanchetta M, et al. The T(–786)C endothelial nitric oxide synthase genotype predicts cardiovascular mortality in high-risk patients J Am Coll Cardiol 2006;48:1166-1174.[Abstract/Free Full Text]2. Laufs U, La FV, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors Circulation 1998;97:1129-1135.[Abstract/Free Full Text] 3. Abe K, Nakayama M, Yoshimura M, et al. Increase in the transcriptional activity of the endothelial nitric oxide synthase gene with fluvastatin: a relation with the –786T>C polymorphism Pharmacogenet Genomics 2005;15:329-336.[Web of Science][Medline] 4. Souza-Costa DC, Sandrim VC, Lopes LF, Gerlach RF, Rego EM, Tanus-Santos JE. Anti-inflammatory effects of atorvastatin: modulation by the T-786C polymorphism in the endothelial nitric oxide synthase gene Atherosclerosis 2007In press. 5. Cesari M, Maiolino G, Colonna S, et al. Under treatment with lipid-lowering drugs of high-risk coronary heart disease patients of the GENICA study J Cardiovasc Pharmacol 2007;42:484-490.[CrossRef] 6. Rossi GP, Taddei S, Virdis A, et al. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients J Am Coll Cardiol 2003;41:938-945.[Abstract/Free Full Text] 7. Cattaruzza M, Guzik TJ, Slodowski W, et al. Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease Circ Res 2004;95:841-847.[Abstract/Free Full Text] 8. Antoniades C, Tousoulis D, Vasiliadou C, et al. Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction J Am Coll Cardiol 2005;46:1101-1109.[Abstract/Free Full Text] 9. Casas JP, Cavalleri GL, Bautista LE, et al. Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review Am J Epidemiol 2006;164:921-935.[Abstract/Free Full Text] 10. Zhang C, Lopez-Ridaura R, Hunter DJ, et al. Common variants of the endothelial nitric oxide synthase gene and the risk of coronary heart disease among U.S. diabetic men Diabetes 2006;55:2140-2147.[Abstract/Free Full Text]
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