Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research
  Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login  
  Home Print this page Email this page Small font sizeDefault font sizeIncrease font size Users Online: 378       

   Table of Contents      
Year : 2011  |  Volume : 133  |  Issue : 5  |  Page : 464-466

Endothelial nitric oxide synthase (eNOS) variants in cardiovascular disease: pharmacogenomic implications

Department of Biochemistry, University College of Science, Osmania University, Hyderabad 500 007, India

Date of Web Publication26-May-2011

Correspondence Address:
Manjula Bhanoori
Department of Biochemistry, University College of Science, Osmania University, Hyderabad 500 007
Login to access the Email id

Source of Support: None, Conflict of Interest: None

PMID: 21623028

Rights and PermissionsRights and Permissions

How to cite this article:
Bhanoori M. Endothelial nitric oxide synthase (eNOS) variants in cardiovascular disease: pharmacogenomic implications. Indian J Med Res 2011;133:464-6

How to cite this URL:
Bhanoori M. Endothelial nitric oxide synthase (eNOS) variants in cardiovascular disease: pharmacogenomic implications. Indian J Med Res [serial online] 2011 [cited 2021 Apr 18];133:464-6. Available from:

The DNA-based information provided by the Human Genome Project, International HapMap Project and the Human Variome project gave an impetus to understanding the nature and consequences of human genetic variations, specifically in conferring susceptibility to common multifactorial diseases [1],[2],[3] . Approximately 20 million sequence variants have been identified by extensive genotyping of common variations among ethnically diverse human populations. The most common human sequence variations are differences in individual base pairs, termed single nucleotide polymorphisms (SNPs). Researchers have discovered many associations between genetic variants in the relevant candidate genes and clinical outcome in diseases such as diabetes, hypertension and cancer [4],[5] . Genome-wide association studies by the Wellcome Trust Case Control Consortium (WTCCC) highlighted the association of SNP markers on chromosome 9p21.3 with coronary artery disease [6] . This was the most significant association seen across the genome for this disease and has been independently replicated in different populations. A number of genetic association studies examined SNPs as these are considered as the primary genetic determinants of the inter-individual variability in susceptibility to disease, response to treatment (pharmacogenetics) and clinical outcomes [7],[8],[9] .

Human cardiovascular disease (CVD) comprises a group of complex diseases which claim over ten million lives annually world wide [10],[11] . CVD includes multifactorial heterogenous conditions such as hypertension, coronary heart disease, stroke, and congestive heart failure. Marked variation in CVD pattern and susceptibility is observed in different populations which can be attributed to genetic and environmental factors. Ethnic differences in responses to cardiovascular drugs such as β-blockers and angiotensin converting enzyme (ACE) inhibitors have been recognized for several decades, and in some cases ethnicity is used in drug therapy decision-making. Studies have reported differential effects of commonly used cardiovascular medications, such as lipid-lowering agents and antihypertensives based on individual variation. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement is well documented across a variety of ethnic populations. Genetic variation can influence both pharmacokinetic and pharmacodynamic mechanisms underlying variation in drug response. Using a candidate gene approach researchers have identified genetic polymorphisms that influence the pharmacodynamic determinants of antihypertensive response. Polymorphisms that have been shown to influence the BP response to diuretics have been identified in candidate genes encoding alpha-adducin (ADD1), subunits of G-proteins (GNB3 and GNAS1), endothelial nitric oxide synthase (eNOS), and ACE [12],[13],[14] .

Vascular endothelial dysfunction is a common characteristic of various cardiovascular diseases. The maintenance of regular vascular tone substantially depends on the bioavailability of endothelium-derived nitric oxide (NO) synthesized by eNOS. The essential role of NO, as the elusive endothelium-derived relaxing factor (EDRF), was the topic of research that won the 1998 Nobel Prize in Physiology or Medicine [15],[16],[17] . The eNOS gene, as a candidate gene in the investigations on hypertension genetics, has attracted the attention of several researchers because of the established role of NO in vascular homeostasis. The eNOS variants located in the 7q35-q36 region have been investigated for their association with CVD, particularly hypertension [18],[19] . Considering the functional roles, relatively high occurrence of minor alleles in different ethnic groups and clinical relevance, three variants, viz., (i) G894T substitution in exon 7 resulting in a Glu to Asp substitution at codon 298 (rs1799983), (ii) an insertion-deletion in intron 4 (4a/b) consisting of two alleles (the a*-deletion which has four tandem 27-bp repeats and the b*-insertion having five repeats), and (iii) a T786C substitution in the promoter region (rs2070744), have been extensively studied [20],[21],[22] . Individual SNPs often cause only a modest change in the resulting gene expression or function. It is, therefore, the concurrent presence of a number of SNPs or haplotypes within a defined region of the chromosome that determines susceptibility to disease development and progression, particularly in case of polygenic diseases [23] .

In the current issue, Shankarishan et al[24] analysed for the first time the prevalence of eNOS exon 7 Glu298Asp polymorphism in tea garden community of North Eastern India, who are a high risk group for CVD. This study also included indigenous Assamese population and found no significant difference between the distribution patterns of eNOS exon 7 Glu298Asp variants between the communities. They have rightly mentioned that for developing public health policies and programmes it is necessary to know the prevalence and distribution of the candidate genes in the population, as well as trends in different population groups. They have also observed that the eNOS exon 7 homozygous GG wild genotype (75.8%) was predominant in the study population followed by heterozygous GT genotype (21.5%) and homozygous TT genotype (2.7%). The frequency distribution of the homozygous GG, heterozygous GT and homozygous mutant TT genotypes were comparable to that of the north Indian and south Indian population. However, the prevalence of GG genotype was found to be low in the study population when compared with other Asian populations. The prevalence of GT genotype was highest among the Italian population (51.8%) and the lowest among the Chinese population (8.3%) and the 'T' allele frequency was found to be relatively higher among the Caucasians and lower among Asian populations [24] . Although this polymorphism is associated with several diseases, indicating its impact on eNOS function and subsequent NO production, its functional significance remains to be better understood. As glutamate and aspartate are conservative replacements, this polymorphism is thought to be a marker for a functional locus elsewhere in the gene. Moreover, there is no consensus on impact of this polymorphism on the enzyme function. Some studies have showed that the Asp variant is more susceptible to inactivation by proteolytic cleavage, possibly due to a tighter turn of the alpha helix, suggesting that homozygosity for this variant may result in impaired catalytic function of eNOS [25] . Conversely, some studies obtained no evidence for altered enzyme function associated with this polymorphism [26] . Therefore, the haplotype analysis considering other polymorphisms within the gene will give better understanding on the implication of this gene as a marker for cardiovascular diseases [27] .

Polymorphisms in the endothelial nitric oxide synthase gene have been associated inconsistently with cardiovascular diseases. Varying distribution of eNOS variants among ethnic groups may explain inter-ethnic differences in nitric oxide mediated vasodilation and response to drugs [28] . Different population studies showed association of eNOS polymorphisms with variations in NO formation and response to drugs [29],[30] . Cardiovascular drugs including statins increase eNOS expression and upregulate NO formation and this effect may be responsible for protective, pleiotropic effects produced by statins [31] . With respect to hypertension, studies have reported interactions between diuretics and polymorphisms in eNOS gene. Particularly, the Glu298Asp polymorphism made a statistically significant contribution to predicting blood pressure response to diuretics [32],[33] . Further progress in this line of research may lead to development of cardiovascular drugs that provide individual based treatment for each patient and the disease mechanism that applies to that patient rather than on the basis of symptoms or in a population based manner.

   References Top

1.Cavalli-Sforza LL. The Human Genome Diversity Project: past, present and future. Nat Rev Genet 2005; 6 : 333-40.  Back to cited text no. 1
2.Crawford DC, Akey DT, Nickerson DA. The patterns of natural variation in human genes. Annu Rev Genomics Hum Genet 2005; 6 : 287-312.  Back to cited text no. 2
3.Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996; 273 : 1516-7.  Back to cited text no. 3
4.Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE, et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001; 293 : 489-93.  Back to cited text no. 4
5.Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008; 118 : 1590-605.  Back to cited text no. 5
6.WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447 : 661-78.  Back to cited text no. 6
7.Chakravati A. To a future of genetic medicine. Nature 2000; 409 : 822-3.  Back to cited text no. 7
8.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 : 1170-5.  Back to cited text no. 8
9.Issa AM. Ethical perspectives on pharmacogenomic profiling in the drug development process. Nat Rev Drug Discovery 2002; 1 : 300-8.  Back to cited text no. 9
10.Sim DS, Lieu H, Andre P. Biomarkers and bioassays for cardiovascular diseases: Present and future. Biomark Insights 2008; 3 : 293-302.  Back to cited text no. 10
11.Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis 2008; 51 : 213-28.  Back to cited text no. 11
12.Schwartz GL, Turner ST. Pharmacogenetics of antihypertensive drug responses. Am J Pharmacogenomics 2004; 4 : 151-60.   Back to cited text no. 12
13.Johnson JA. Ethnic differences in cardiovascular drug response: rotential contribution of pharmacogenetics. Circulation 2008; 118 : 1383-93.  Back to cited text no. 13
14.Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353 : 717-9.   Back to cited text no. 14
15.Smith O. Nobel Prize for NO research. Nat Med 1998; 4 : 1215.   Back to cited text no. 15
16.Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 1997; 48 : 489-509.  Back to cited text no. 16
17.Dudzinski DM, Igarashi J, Greif DM, Michel T. The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol 2006; 46 : 235-76.  Back to cited text no. 17
18.Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377 : 239-42.   Back to cited text no. 18
19.Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007; 115 : 1285-95.   Back to cited text no. 19
20.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 : 921-35.   Back to cited text no. 20
21.Hingorani AD. Polymorphisms in endothelial nitric oxide synthase and atherogenesis: John French Lecture 2000. Atherosclerosis 2001; 154 : 521-7.  Back to cited text no. 21
22.Zintzaras E, Kitsios G, Stefanidis I. Endothelial NO synthase gene polymorphisms and hypertension: a meta-analysis. Hypertension 2006; 48 : 700-10.   Back to cited text no. 22
23.Cardon LR, Bell JL. Association study designs for complex diseases. Nat Rev Genet 2001; 2 : 91-9.  Back to cited text no. 23
24.Shankarishan P, Borah PK, Ahmed G, Mahanta J. Prevalence of endothelial nitric oxide synthase (eNOS) gene exon 7 Glu298Asp variant in North Eastern India. Indian J Med Res 2011; 133 : 487-91.  Back to cited text no. 24
25.Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 2000; 97 : 2832-5.   Back to cited text no. 25
26.Fairchild TA, Fulton D, Fontana JT, Gratton JP, McCabe TJ, Sessa WC. Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)!Asp variant of human endothelial nitric-oxide synthase. J Biol Chem 2001; 276 : 26674-9.  Back to cited text no. 26
27.Metzger IF, Sertorio JT, Tanus-Santos JE. Modulation of nitric oxide formation by endothelial nitric oxide synthase gene halotypes. Free Radic Biol Med 2007; 43 : 987-92.  Back to cited text no. 27
28.Tanus-Santos JE, Desai M, Flockhart DA. Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics 2001; 11 : 719-25.  Back to cited text no. 28
29.Ignarro LJ, Napoli C, Loscalzo J. Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ Res 2002; 90 : 21-8.   Back to cited text no. 29
30.Leeson CP, Hingorani AD, Mullen MJ, Jeerooburkhan N, Kattenhorn M, Cole TJ, et al. Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function. Circ Res 2002; 90 : 1153-8.   Back to cited text no. 30
31.Lacchini R, Silva PS, Tanus-Santos JE. A pharmacogenetics-based approach to reduce cardiovascular mortality with the prophylactic use of statins. Basic Clin Pharmacol Toxicol 2010; 106 : 357-61.   Back to cited text no. 31
32.Turner ST, Chapman AB, Schwartz GL, Boerwinkle E. Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide. Am J Hypertens 2003; 16 : 834-9.  Back to cited text no. 32
33.Cooke GE, Doshi A, Binkley PF Endothelial nitric oxide synthase gene: prospects for treatment of heart disease. Pharmacogenomics 2007; 8 : 1723-34.  Back to cited text no. 33


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article

 Article Access Statistics
    PDF Downloaded292    
    Comments [Add]    

Recommend this journal