Genetic Mechanisms Possibly Leading to Racially Different Responses to Nitrate Therapy




Ferdinand et al have written a very important and insightful review article summarizing strong evidence recommending combined isosorbide dinitrate and hydralazine therapy to reduce mortality and morbidity for African-Americans with heart failure and reduced ejection fraction. The investigators have correctly pointed out that more genetic information is necessary to assess the impact of many other polymorphisms that may affect drug response. We would like to add important information that is relevant to nitric oxide (NO) biology and may help to explain mechanisms possibly involved in racial differences observed when patients receive isosorbide dinitrate and hydralazine, which are drugs that directly or indirectly affect NO activity. There is now evidence that combinations of genetic polymorphisms (haplotypes) in the gene encoding endothelial NO synthase (eNOS) may be more informative than single eNOS polymorphisms with respect to endogenous NO formation and bioavailability. Importantly, a specific eNOS gene haplotype combining particular eNOS gene variants (C-Glu-b) is associated with lower levels of both nitrate and nitrite, which are products of NO metabolism and reflect endogenous NO formation. This association has been reported in both white and black subjects, although major differences exist in the distribution of haplotype frequency when whites and blacks are compared. This eNOS haplotype apparently predisposes to hypertension in obese children and adolescents, although different eNOS haplotypes have been associated with hypertension in adults. In line with the suggestion by Ferdinand et al, it remains to be determined which eNOS haplotypes may predict the responses to isosorbide dinitrate and hydralazine therapy, particularly in African-Americans. In addition, there is evidence that black subjects have higher circulating concentrations of an endogenous NOS inhibitor, the asymmetric dimethylarginine, and therefore, black subjects may be exposed to additional factors impairing endogenous NO formation that are counteracted by isosorbide dinitrate and hydralazine therapy. The improved responses of black subjects to isosorbide dinitrate and hydralazine therapy may suggest severely disrupted vascular homeostasis in these subjects, which may be particularly responsive to nitrate therapy.


References



  1. 1. Ferdinand K.C., Elkayam U., Mancini D., Ofili E., Pina I., Anand I., Feldman A., McNamara D., and Leggett C.: Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the African-American Heart Failure Trial. Am J Cardiol 2014; 114: pp. 151-159

  2. 2. Metzger I.F., Sertorio J.T., and Tanus-Santos J.E.: Modulation of nitric oxide formation by endothelial nitric oxide synthase gene haplotypes. Free Radic Biol Med 2007; 43: pp. 987-992

  3. 3. Metzger I.F., Souza-Costa D.C., Marroni A.S., Nagassaki S., Desta Z., Flockhart D.A., and Tanus-Santos J.E.: Endothelial nitric oxide synthase gene haplotypes associated with circulating concentrations of nitric oxide products in healthy men. Pharmacogenet Genomics 2005; 15: pp. 565-570

  4. 4. Metzger I.F., Ishizawa M.H., Rios-Santos F., Carvalho W.A., and Tanus-Santos J.E.: Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. Pharmacogenomics J 2011; 11: pp. 393-399

  5. 5. Marroni A.S., Metzger I.F., Souza-Costa D.C., Nagassaki S., Sandrim V.C., Correa R.X., Rios-Santos F., and Tanus-Santos J.E.: Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase genetic polymorphisms. Nitric Oxide 2005; 12: pp. 177-182

  6. 6. Tanus-Santos J.E., Desai M., and Flockhart D.A.: Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics 2001; 11: pp. 719-725

  7. 7. Souza-Costa D.C., Belo V.A., Silva P.S., Sertorio J.T., Metzger I.F., Lanna C.M., Machado M.A., and Tanus-Santos J.E.: eNOS haplotype associated with hypertension in obese children and adolescents. Int J Obes (Lond) 2011; 35: pp. 387-392

  8. 8. Sandrim V.C., Coelho E.B., Nobre F., Arado G.M., Lanchote V.L., and Tanus-Santos J.E.: Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis 2006; 186: pp. 428-432

  9. 9. Sandrim V.C., de Syllos R.W., Lisboa H.R., Tres G.S., and Tanus-Santos J.E.: Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus. Atherosclerosis 2006; 189: pp. 241-246

  10. 10. Sandrim V.C., de Syllos R.W., Lisboa H.R., Tres G.S., and Tanus-Santos J.E.: Influence of eNOS haplotypes on the plasma nitric oxide products concentrations in hypertensive and type 2 diabetes mellitus patients. Nitric Oxide 2007; 16: pp. 348-355

  11. 11. Melikian N., Wheatcroft S.B., Ogah O.S., Murphy C., Chowienczyk P.J., Wierzbicki A.S., Sanders T.A., Jiang B., Duncan E.R., Shah A.M., and Kearney M.T.: Asymmetric dimethylarginine and reduced nitric oxide bioavailability in young Black African men. Hypertension 2007; 49: pp. 873-877

  12. 12. Sandrim V.C., Palei A.C., Metzger I.F., Cavalli R.C., Duarte G., and Tanus-Santos J.E.: Interethnic differences in ADMA concentrations and negative association with nitric oxide formation in preeclampsia. Clin Chim Acta 2010; 411: pp. 1457-1460

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Dec 1, 2016 | Posted by in CARDIOLOGY | Comments Off on Genetic Mechanisms Possibly Leading to Racially Different Responses to Nitrate Therapy

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