Thrombosis Research 134 (2014) 1160–1161
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Endothelial nitric oxide synthase - regulation and clinical relevance
Dear Editors, In this issue Zhao et al. [1] performing a meta-analysis of 17 studies investigating the association between G894T polymorphism and thrombotic disease are reporting significant results despite significant heterogeneity. The subgroup analysis stratified by diagnosis and ethnicity revealed an increased risk without heterogeneity for venous thrombosis by eNOS G894T polymorphism in the Asian population but in contrast to others [2] not to (carotid) atherosclerosis. Endothelial nitric oxide (NO) production plays a key role in regulating arterial tone, haemostatic balancing and protecting the arterial wall from atherosclerosis. Functional NO deficiency is an early event in cardiovascular disease [3] caused by a complex interplay of genetic, environmental, life-style and risk factors, their relative importance being unknown. Endothelial nitric oxide synthase (eNOS) gene polymorphism has been associated with the pathogenesis of a great variety of cardiovascular diseases but also many conditions causing an increased risk for its development [4,5]. The gene coding for eNOS is located on chromosome 7. Genetic alterations in the gene encoding for eNOS apparently are contributing to a great extent to the development and progression of vascular disease, for example an eNOS intron 4 polymorphism was associated with vascular disease, revealed a difference between African-Americans and Caucasians, however, surprisingly, did not result in endothelial function changes [6]. Metzger [7] found no influence of individual eNOS polymorphism on vascular NO-formation while certain haplotypes were associated with an altered NO-production [8]. No reliable human biochemical data are available concerning the role on arterial tree vs. venous system. The association of vascular NO-formation and eNOS G894T variation [9] with hyperhomocysteinemia has been described. The potential influence of malignoma associated paraneoplasia and the concomitant change in homocysteine is known [10], but its strength still needs to be confirmed. These important influencing factors have not been considered. Concerning NO-formation at least defining genetic markers seems to be more relevant than ethnic classification. eNOS polymorphism may affect NO-synthesis, NO-mediated effects and drug response, for example Indians from the Brazilian Amazon showed a much lower genetic diversity as compared to blacks or whites living in the same country. Apparently, different eNOS haplotypes are associated with a varying susceptibility to various cardiovascular diseases [11–13]. There are a variety of genetic variations for eNOS having been already reported to be of pathogenetic relevance for atherothrombosis. Performing a meta-analysis of the association of one of these eNOS polymorphisms, G894T reveals an enhanced risk of venous thrombosis. To elucidate the complex biochemical interplay with the multitude of interfering agents by means of statistical analysis seems to be impossible. The information on eNOS polymorphism definitely is of great
http://dx.doi.org/10.1016/j.thromres.2014.08.011 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
scientific interest but contradicts earlier findings concerning the role on the arterial tree [11,13]. Despite the statistical limitations of the study listed by the authors [1] and the undoubted mass strategic value, the question of the clinical prognostic value for an individual remains. eNOS activity is regulated genetically as well as by agonists acting on G-protein associated receptors [14] and many factors such as mechanical stress, risk factors, hormones, growth factors, drugs and a variety of other agents. eNOS shows a significant up- and down-regulation depending on exogenous influencing factors. There is also a huge complexity of interactions with numerous molecular targets. The prognostic value of eNOS polymorphism thus remains to be assessed in controlled prospective trials with special consideration of the ethnic background. As long as the strength is not proven, for an individual patient at present the influence of eNOS polymorphism may be much less relevant as compared to the many factors directly and indirectly affecting NO-synthesis in-vivo.
Conflict of interest There is no conflict of interest.
References [1] Zhao L, Li C, Yin Q, Zhang Q, Shao R, Fang Y. Endothelial nitric oxide synthase 894 G N T polymorphism and thrombotic disease: A Meta-Analysis of 17 studies involving 8808 subjects. Thromb Res 2014;134:1057–65 (in this issue). [2] Wolff B, Braun C, Schluter C, Grabe HJ, Popowski K, Volzke H, et al. Endothelial nitric oxide synthase Glu(298)– N Asp polymorphism, carotid atherosclerosis and intimamedia thickness in a general population sample. Clin Sci 2005;109:475–81. [3] Zeiher AM, Drexler H, Wollschläger H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991;84:1984–92. [4] Galluccio E, Piatti P, Citterio L, Lucotti PC, Setola E, Cassina L, et al. Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis. Am J Physiol Endocrinol Metab 2008;294:E978–86. [5] Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, et al. Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes 2003;52:1270–5. [6] Rao S, Austin H, Davidoff MN, Zafari AM. Endothelial nitric oxide synthase intron 4 polymorphism is a marker for coronary artery disease in African-American and Caucasian men. Ethn Dis 2005;15:191–7. [7] Metzger IF, Ishizawa MH, Rios-Santos F, Carvalho WA, Tanus-Santos JE. Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. Pharmacogenomics J 2011;11:393–9. [8] Martinelli NC, Santos KG, Biolo A, La Porta VL, Cohen CR, Silvello D, et al. Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: an haplotype analysis. Nitric Oxide 2012;26:141–7. [9] Heil SG, Den Heijer M, Van der Rijt-Pisa BJ, Kluijtmans LA, Blom HJ. The 894 N T variant of endothelial nitric oxide synthase (eNOS) increases the risk of venous thrombosis through interaction with elevated homocysteine levels. J Thromb Haemost 2004;2:750–3. [10] Aleksic D, Djokic D, Golubicic I, Jakovljevic V, Djuric D. The importance of the blood levels of homocysteine, folic acid and vitamin B12 in children with malignant diseases. J BUON 2013;18:1019–25. [11] Fujihara J, Yasuda T, Kawai Y, Morikawa N, Arakawa K, Koda Y, et al. First survey of the three gene polymorphisms (PON1 Q192R, eNOS E298D and eNOS C-786T) potentially associated with coronary artery spasm in African populations and comparison with worldwide data. Cell Biochem Funct 2011;29:156–63.
Letter to the Editors-in-Chief [12] Luizon MR, Izidoro-Toledo TC, Simoes AL, Tanus-Santos JE. Endothelial nitric oxide synthase polymorphisms and haplotypes in Amerindians. DNA Cell Biol 2009;28: 329–34. [13] Bhuiyan AR, Chen W, Srinivasan SR, Rice JC, Mock NB, Tang R, et al. Interaction of G-protein beta3 subunit and nitric oxide synthase gene polymorphisms on carotid artery intima-media thickness in young adults: the Bogalusa Heart Study. Am J Hypertens 2008;21:917–21. [14] Knowles RG, Moncada S. Nitric oxide synthesis in mammals. Biochem J 1994;298: 249–58.
Helmut Sinzinger Wilhelm Auerswald Atherosclerosis Research Group, Vienna, Austria Institute Athos, Vienna, Austria Corresponding author at: Wilhelm Auerswald Atherosclerosis Research Group, Vienna, Austria. Tel.: +43 14082633; fax: +43 14081366. E-mail address: [email protected].
1161
Robert Berent Center for Cardiovascular Rehabilitation, Bad Ischl, Austria 4 August 2014
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Endothelial nitric oxide synthase - regulation and clinical relevance
Dear Editors, In this issue Zhao et al. [1] performing a meta-analysis of 17 studies investigating the association between G894T polymorphism and thrombotic disease are reporting significant results despite significant heterogeneity. The subgroup analysis stratified by diagnosis and ethnicity revealed an increased risk without heterogeneity for venous thrombosis by eNOS G894T polymorphism in the Asian population but in contrast to others [2] not to (carotid) atherosclerosis. Endothelial nitric oxide (NO) production plays a key role in regulating arterial tone, haemostatic balancing and protecting the arterial wall from atherosclerosis. Functional NO deficiency is an early event in cardiovascular disease [3] caused by a complex interplay of genetic, environmental, life-style and risk factors, their relative importance being unknown. Endothelial nitric oxide synthase (eNOS) gene polymorphism has been associated with the pathogenesis of a great variety of cardiovascular diseases but also many conditions causing an increased risk for its development [4,5]. The gene coding for eNOS is located on chromosome 7. Genetic alterations in the gene encoding for eNOS apparently are contributing to a great extent to the development and progression of vascular disease, for example an eNOS intron 4 polymorphism was associated with vascular disease, revealed a difference between African-Americans and Caucasians, however, surprisingly, did not result in endothelial function changes [6]. Metzger [7] found no influence of individual eNOS polymorphism on vascular NO-formation while certain haplotypes were associated with an altered NO-production [8]. No reliable human biochemical data are available concerning the role on arterial tree vs. venous system. The association of vascular NO-formation and eNOS G894T variation [9] with hyperhomocysteinemia has been described. The potential influence of malignoma associated paraneoplasia and the concomitant change in homocysteine is known [10], but its strength still needs to be confirmed. These important influencing factors have not been considered. Concerning NO-formation at least defining genetic markers seems to be more relevant than ethnic classification. eNOS polymorphism may affect NO-synthesis, NO-mediated effects and drug response, for example Indians from the Brazilian Amazon showed a much lower genetic diversity as compared to blacks or whites living in the same country. Apparently, different eNOS haplotypes are associated with a varying susceptibility to various cardiovascular diseases [11–13]. There are a variety of genetic variations for eNOS having been already reported to be of pathogenetic relevance for atherothrombosis. Performing a meta-analysis of the association of one of these eNOS polymorphisms, G894T reveals an enhanced risk of venous thrombosis. To elucidate the complex biochemical interplay with the multitude of interfering agents by means of statistical analysis seems to be impossible. The information on eNOS polymorphism definitely is of great
http://dx.doi.org/10.1016/j.thromres.2014.08.011 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
scientific interest but contradicts earlier findings concerning the role on the arterial tree [11,13]. Despite the statistical limitations of the study listed by the authors [1] and the undoubted mass strategic value, the question of the clinical prognostic value for an individual remains. eNOS activity is regulated genetically as well as by agonists acting on G-protein associated receptors [14] and many factors such as mechanical stress, risk factors, hormones, growth factors, drugs and a variety of other agents. eNOS shows a significant up- and down-regulation depending on exogenous influencing factors. There is also a huge complexity of interactions with numerous molecular targets. The prognostic value of eNOS polymorphism thus remains to be assessed in controlled prospective trials with special consideration of the ethnic background. As long as the strength is not proven, for an individual patient at present the influence of eNOS polymorphism may be much less relevant as compared to the many factors directly and indirectly affecting NO-synthesis in-vivo.
Conflict of interest There is no conflict of interest.
References [1] Zhao L, Li C, Yin Q, Zhang Q, Shao R, Fang Y. Endothelial nitric oxide synthase 894 G N T polymorphism and thrombotic disease: A Meta-Analysis of 17 studies involving 8808 subjects. Thromb Res 2014;134:1057–65 (in this issue). [2] Wolff B, Braun C, Schluter C, Grabe HJ, Popowski K, Volzke H, et al. Endothelial nitric oxide synthase Glu(298)– N Asp polymorphism, carotid atherosclerosis and intimamedia thickness in a general population sample. Clin Sci 2005;109:475–81. [3] Zeiher AM, Drexler H, Wollschläger H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991;84:1984–92. [4] Galluccio E, Piatti P, Citterio L, Lucotti PC, Setola E, Cassina L, et al. Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis. Am J Physiol Endocrinol Metab 2008;294:E978–86. [5] Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, et al. Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes 2003;52:1270–5. [6] Rao S, Austin H, Davidoff MN, Zafari AM. Endothelial nitric oxide synthase intron 4 polymorphism is a marker for coronary artery disease in African-American and Caucasian men. Ethn Dis 2005;15:191–7. [7] Metzger IF, Ishizawa MH, Rios-Santos F, Carvalho WA, Tanus-Santos JE. Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. Pharmacogenomics J 2011;11:393–9. [8] Martinelli NC, Santos KG, Biolo A, La Porta VL, Cohen CR, Silvello D, et al. Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: an haplotype analysis. Nitric Oxide 2012;26:141–7. [9] Heil SG, Den Heijer M, Van der Rijt-Pisa BJ, Kluijtmans LA, Blom HJ. The 894 N T variant of endothelial nitric oxide synthase (eNOS) increases the risk of venous thrombosis through interaction with elevated homocysteine levels. J Thromb Haemost 2004;2:750–3. [10] Aleksic D, Djokic D, Golubicic I, Jakovljevic V, Djuric D. The importance of the blood levels of homocysteine, folic acid and vitamin B12 in children with malignant diseases. J BUON 2013;18:1019–25. [11] Fujihara J, Yasuda T, Kawai Y, Morikawa N, Arakawa K, Koda Y, et al. First survey of the three gene polymorphisms (PON1 Q192R, eNOS E298D and eNOS C-786T) potentially associated with coronary artery spasm in African populations and comparison with worldwide data. Cell Biochem Funct 2011;29:156–63.
Letter to the Editors-in-Chief [12] Luizon MR, Izidoro-Toledo TC, Simoes AL, Tanus-Santos JE. Endothelial nitric oxide synthase polymorphisms and haplotypes in Amerindians. DNA Cell Biol 2009;28: 329–34. [13] Bhuiyan AR, Chen W, Srinivasan SR, Rice JC, Mock NB, Tang R, et al. Interaction of G-protein beta3 subunit and nitric oxide synthase gene polymorphisms on carotid artery intima-media thickness in young adults: the Bogalusa Heart Study. Am J Hypertens 2008;21:917–21. [14] Knowles RG, Moncada S. Nitric oxide synthesis in mammals. Biochem J 1994;298: 249–58.
Helmut Sinzinger Wilhelm Auerswald Atherosclerosis Research Group, Vienna, Austria Institute Athos, Vienna, Austria Corresponding author at: Wilhelm Auerswald Atherosclerosis Research Group, Vienna, Austria. Tel.: +43 14082633; fax: +43 14081366. E-mail address: [email protected].
1161
Robert Berent Center for Cardiovascular Rehabilitation, Bad Ischl, Austria 4 August 2014
