Abstract
Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been associated with variations in nitric oxide (NO) formation and response to drugs in white subjects. We examined whether genetic polymorphisms (T-786C, b/a intron 4 and Glu298Asp) and haplotypes of the eNOS gene affect NO formation in 179 healthy black subjects. To assess NO formation, we measured the concentrations of nitrite in the plasma, red blood cells and whole blood. Although we found no effects of individual eNOS polymorphisms on NO formation, we found that the ‘C-4b-Glu’ haplotype is significantly more common in subjects with low circulating plasma and whole blood nitrite concentrations compared with subjects with high circulating nitrite concentrations (both P<0.0007). These findings reproduce previous findings in white subjects and are consistent with the idea that defining genetic markers is more important than ethnic classification, at least in terms of NO formation.
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References
Moncada S, Higgs EA . Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest 1991; 21: 361–374.
Wang X, Tanus-Santos JE, Reiter CD, Dejam A, Shiva S, Smith RD et al. Biological activity of nitric oxide in the plasmatic compartment. Proc Natl Acad Sci USA 2004; 101: 11477–11482.
Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9: 1498–1505.
Nagassaki S, Herculano RD, Graeff CF, Tanus-Santos JE . eNOS T-786C polymorphism affects atorvastatin-induced changes in erythrocyte membrane fluidity. Eur J Clin Pharmacol 2009; 65: 385–392.
Nagassaki S, Sertorio JT, Metzger IF, Bem AF, Rocha JB, Tanus-Santos JE . eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite. Free Radic Biol Med 2006; 41: 1044–1049.
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; 193: 438–444.
Yancy CW . Race-based therapeutics. Curr Hypertens Rep 2008; 10: 276–285.
McNamara DM . Emerging role of pharmacogenomics in heart failure. Curr Opin Cardiol 2008; 23: 261–268.
Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ et al. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 2003; 348: 1170–1175.
Luizon MR, Izidoro-Toledo TC, Simoes AL, Tanus-Santos JE . Endothelial nitric oxide synthase polymorphisms and haplotypes in Amerindians. DNA Cell Biol 2009; 28: 329–334.
Marroni AS, Metzger IF, Souza-Costa DC, Nagassaki S, Sandrim VC, Correa RX et al. Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase genetic polymorphisms. Nitric Oxide 2005; 12: 177–182.
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.
McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Venkitachalam L et al. Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial. J Card Fail 2009; 15: 191–198.
Metzger IF, Sertorio JT, Tanus-Santos JE . Modulation of nitric oxide formation by endothelial nitric oxide synthase gene haplotypes. Free Radic Biol Med 2007; 43: 987–992.
Metzger IF, Souza-Costa DC, Marroni AS, Nagassaki S, Desta Z, Flockhart DA 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.
Dejam A, Hunter CJ, Pelletier MM, Hsu LL, Machado RF, Shiva S et al. Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 2005; 106: 734–739.
Sambrook J, Russell DW . Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press: New York, 2001.
Sandrim VC, Palei AC, Cavalli RC, Araujo FM, Ramos ES, Duarte G et al. eNOS haplotypes associated with gestational hypertension or preeclampsia. Pharmacogenomics 2008; 9: 1467–1473.
Metzger IF, Sertorio JT, Tanus-Santos JE . Relationship between systemic nitric oxide metabolites and cyclic GMP in healthy male volunteers. Acta Physiol (Oxf) 2006; 188: 123–127.
Demacq C, Metzger IF, Gerlach RF, Tanus-Santos JE . Inverse relationship between markers of nitric oxide formation and plasma matrix metalloproteinase-9 levels in healthy volunteers. Clin Chim Acta 2008; 394: 72–76.
Souza-Costa DC, Zerbini T, Metzger IF, Rocha JB, Gerlach RF, Tanus-Santos JE . l-Arginine attenuates acute pulmonary embolism-induced oxidative stress and pulmonary hypertension. Nitric Oxide 2005; 12: 9–14.
Stephens M, Donnelly P . A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.
Gladwin MT, Raat NJ, Shiva S, Dezfulian C, Hogg N, Kim-Shapiro DB et al. Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 2006; 291: H2026–H2035.
Gladwin MT, Crawford JH, Patel RP . The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation. Free Radic Biol Med 2004; 36: 707–717.
Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A . Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA 2004; 101: 13683–13688.
Bryan NS, Calvert JW, Elrod JW, Gundewar S, Ji SY, Lefer DJ . Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci USA 2007; 104: 19144–19149.
Kehmeier ES, Kropp M, Kleinbongard P, Lauer T, Balzer J, Merx MW et al. Serial measurements of whole blood nitrite in an intensive care setting. Free Radic Biol Med 2008; 44: 1945–1950.
Kleinbongard P, Dejam A, Lauer T, Jax T, Kerber S, Gharini P et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 2006; 40: 295–302.
Casas JP, Cavalleri GL, Bautista LE, Smeeth L, Humphries SE, Hingorani AD . Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review. Am J Epidemiol 2006; 164: 921–935.
Cooke GE, Doshi A, Binkley PF . Endothelial nitric oxide synthase gene: prospects for treatment of heart disease. Pharmacogenomics 2007; 8: 1723–1734.
Murphy C, Kanaganayagam GS, Jiang B, Chowienczyk PJ, Zbinden R, Saha M et al. Vascular dysfunction and reduced circulating endothelial progenitor cells in young healthy UK South Asian men. Arterioscler Thromb Vasc Biol 2007; 27: 936–942.
Rosenbaum DA, Pretorius M, Gainer JV, Byrne D, Murphey LJ, Painter CA et al. Ethnicity affects vasodilation, but not endothelial tissue plasminogen activator release, in response to bradykinin. Arterioscler Thromb Vasc Biol 2002; 22: 1023–1028.
Fenster CP, Darley-Usmar VM, Landar AL, Gower BA, Weinsier RL, Hunter GR et al. Weight loss and race modulate nitric oxide metabolism in overweight women. Free Radic Biol Med 2004; 37: 695–702.
Ke RW, Todd Pace D, Ahokas RA . Effect of short-term hormone therapy on oxidative stress and endothelial function in African American and Caucasian postmenopausal women. Fertil Steril 2003; 79: 1118–1122.
Stein CM, Lang CC, Nelson R, Brown M, Wood AJ . Vasodilation in black Americans: attenuated nitric oxide-mediated responses. Clin Pharmacol Ther 1997; 62: 436–443.
Sareli P, Radevski IV, Valtchanova ZP, Libhaber E, Candy GP, Den Hond E et al. Efficacy of different drug classes used to initiate antihypertensive treatment in black subjects: results of a randomized trial in Johannesburg, South Africa. Arch Intern Med 2001; 161: 965–971.
Kalinowski L, Dobrucki IT, Malinski T . Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation 2004; 109: 2511–2517.
Li R, Lyn D, Lapu-Bula R, Oduwole A, Igho-Pemu P, Lankford B et al. Relation of endothelial nitric oxide synthase gene to plasma nitric oxide level, endothelial function, and blood pressure in African Americans. Am J Hypertens 2004; 17: 560–567.
Sandrim VC, Coelho EB, Nobre F, Arado GM, Lanchote VL, Tanus-Santos JE . Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis 2006; 186: 428–432.
Sandrim VC, de Syllos RW, Lisboa HR, Tres GS, Tanus-Santos JE . Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus. Atherosclerosis 2006; 189: 241–246.
Sandrim VC, de Syllos RW, Lisboa HR, Tres GS, Tanus-Santos JE . Influence of eNOS haplotypes on the plasma nitric oxide products concentrations in hypertensive and type 2 diabetes mellitus patients. Nitric Oxide 2007; 16: 348–355.
Sandrim VC, Palei AC, Luizon MR, Izidoro-Toledo TC, Cavalli RC, Tanus-Santos JE . eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension. Pharmacogenomics J 2010; 10: 40–45.
Acknowledgements
This study was supported by Fundação de Amparo à Pesquisa do Estado de Sao Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
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Metzger, I., Ishizawa, M., Rios-Santos, F. et al. Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. Pharmacogenomics J 11, 393–399 (2011). https://doi.org/10.1038/tpj.2010.52
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DOI: https://doi.org/10.1038/tpj.2010.52
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