CORRESPONDENCE: LETTER TO THE EDITOR
Cardiovascular Mortality in High-Risk Patients and T-786C Polymorphism in Promoter Region of the Endothelial Nitric Oxide Synthase Gene
Jose Eduardo Tanus-Santos, MD, PhD* and
Antonio Casella-Filho, MD, MSc
* Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil (Email: tanus{at}fmrp.usp.br).
Rossi et al. (1) reported very interesting and intriguing results of the first prospective study examining the possible effects of 2 single nucleotide polymorphisms (SNP) in the endothelial nitric oxide synthase (eNOS) gene (the T-786C SNP in the promoter region, and the G894T SNP in exon 7) on cardiovascular mortality among high-risk patients. Although no significant effects were found for the G894T SNP, more cardiovascular deaths were found when individuals with TT genotype for the T-786C SNP were compared with CC + CT individuals (1). The significant effect of T-786C SNP on cardiovascular mortality persisted even after many confounding factors were taken into consideration. However, a significant number of individuals (32%) were on lipid-lowering therapy at recruitment (1), and it is probable that an increased proportion of these subjects may have received statins thereafter.
Interestingly, although the T-786C SNP apparently does not significantly affect nitric oxide (NO) availability (2,3), it may modulate the responses to statins. In this regard, we have recently reported that treatment with atorvastatin significantly increased NO availability (measured as whole blood nitrite) in CC individuals, but not in TT individuals (4), thus confirming previous findings suggesting that statins may produce stronger effects on NO availability in CC individuals compared with TT individuals (5). In addition, atorvastatin significantly reduced the concentrations of inflammatory markers in subjects with CC (but not TT) genotype (6). Although these findings derive from studies that included healthy individuals, they suggest that statins may significantly modify the cardiovascular risk associated with the T-786C SNP. Indeed, it is possible that treatment with statins counteracts the effects associated with the T-786C SNP (4), thus leading to apparently paradoxical results such as those reported by Rossi et al. (1).
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References
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- 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]
- Nagassaki S, Metzger IF, Souza-Costa DC, Marroni AS, Uzuelli JA, Tanus-Santos JE. eNOS genotype is without effect on circulating nitrite/nitrate level in healthy male population Thromb Res 2005;115:375-379.[CrossRef][ISI][Medline]
- Metzger IF, Souza-Costa DC, Marroni AS, et al. Endothelial nitric oxide synthase gene haplotypes associated with circulating concentrations of nitric oxide products in healthy men Pharmacogenet Genomics 2005;15:565-570.[ISI][Medline]
- Nagassaki S, Sertorio JTC, Metzger IF, Bern AF, Rocha JBT, Tanus-Santos JE. eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite Free Radic Biol Med 2006;41:1044-1049.[CrossRef][ISI][Medline]
- 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.[ISI][Medline]
- 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 2007.
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