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  1. Gan YY, Chen CF
    Biochem Genet, 2012 Feb;50(1-2):52-62.
    PMID: 21927815 DOI: 10.1007/s10528-011-9458-0
    Human endothelial nitric oxide synthase (eNOS) is one isoform of the nitric oxide synthases that are responsible for nitric oxide synthesis from L-arginine. The gene encoding eNOS contains a 27-bp VNTR polymorphism in intron 4. We report here for the first time the presence of a novel allele 3, which was absent in all other populations studied to date, in 1.7% each of Singaporean Indians and Malays. We also detected the presence of a novel genotype 3/5 in 3.4% each of Singaporean Indians and Malays. Allele 6, which was absent in Han Chinese from northern China and Taiwan and was also absent in Indians from the Indian subcontinent, was found in 2.1% of Singaporean Chinese and in 0.3% of Singaporean Indians.
    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
  2. Loo KW, Griffiths LR, Gan SH
    BMC Med Genet, 2012 May 17;13:34.
    PMID: 22594584 DOI: 10.1186/1471-2350-13-34
    BACKGROUND: Hyperhomocysteinemia as a consequence of the MTHFR 677 C > T variant is associated with cardiovascular disease and stroke. Another factor that can potentially contribute to these disorders is a depleted nitric oxide level, which can be due to the presence of eNOS +894 G > T and eNOS -786 T > C variants that make an individual more susceptible to endothelial dysfunction. A number of genotyping methods have been developed to investigate these variants. However, simultaneous detection methods using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis are still lacking. In this study, a novel multiplex PCR-RFLP method for the simultaneous detection of MTHFR 677 C > T and eNOS +894 G > T and eNOS -786 T > C variants was developed. A total of 114 healthy Malay subjects were recruited. The MTHFR 677 C > T and eNOS +894 G > T and eNOS -786 T > C variants were genotyped using the novel multiplex PCR-RFLP and confirmed by DNA sequencing as well as snpBLAST. Allele frequencies of MTHFR 677 C > T and eNOS +894 G > T and eNOS -786 T > C were calculated using the Hardy Weinberg equation.

    METHODS: The 114 healthy volunteers were recruited for this study, and their DNA was extracted. Primer pair was designed using Primer 3 Software version 0.4.0 and validated against the BLAST database. The primer specificity, functionality and annealing temperature were tested using uniplex PCR methods that were later combined into a single multiplex PCR. Restriction Fragment Length Polymorphism (RFLP) was performed in three separate tubes followed by agarose gel electrophoresis. PCR product residual was purified and sent for DNA sequencing.

    RESULTS: The allele frequencies for MTHFR 677 C > T were 0.89 (C allele) and 0.11 (T allele); for eNOS +894 G > T, the allele frequencies were 0.58 (G allele) and 0.43 (T allele); and for eNOS -786 T > C, the allele frequencies were 0.87 (T allele) and 0.13 (C allele).

    CONCLUSIONS: Our PCR-RFLP method is a simple, cost-effective and time-saving method. It can be used to successfully genotype subjects for the MTHFR 677 C > T and eNOS +894 G > T and eNOS -786 T > C variants simultaneously with 100% concordance from DNA sequencing data. This method can be routinely used for rapid investigation of the MTHFR 677 C > T and eNOS +894 G > T and eNOS -786 T > C variants.

    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
  3. Mehdi WA, Mehde AA, Yusof F, Raus RA, Resen AK, Ghazali H
    Int J Biol Macromol, 2019 Nov 01;140:719-726.
    PMID: 31445152 DOI: 10.1016/j.ijbiomac.2019.08.184
    BACKGROUND: The genetic features indicate a crucial role in nephrolithiasis. The present study was aimed to investigate the role of Glutathione-S-transferase Mu (GSTM1), Glutathione-S- transferase Theta (GSTT1) and endothelial nitric oxide synthase (eNOs) gene polymorphism in nephrolithiasis.

    METHODS: We involved a case-control study in which 480 individuals were divided into 240 healthy control and 240 patients with nephrolithiasis. For each patient and control, we measured biochemical criteria, levels of glutathione S-transferase, eNOs, GSTM1, GSTT1genes and eNOS genes polymorphism by PCR-RFLP.

    RESULTS: GSTM1 and GSTT1 null genotypes are not a risk features for nephrolithiasis. The eNOS frequency GG, GT, and TT genotypes by using Ban II enzyme as restriction enzyme were found to be (48.33, 36.67, and 15.00) %. The eNOS frequency TT, GT, and GG genotypes by using the Ban II enzyme as restriction enzyme were found to be 15.84, 25.83, and 58.33%, respectively. The result showed an increase in serum eNOs levels were in the patient's group comparing to control.

    CONCLUSIONS: This work is the first in the literature to study the relation between eNOs genes polymorphisms and nephrolithiasis. The results conclude that TT genotypes in the eNOs genes are associated with an increase the oxidative stress in patients.

    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
  4. Rasool AH, Ghazali DM, Abdullah H, Halim AS, Wong AR
    Microvasc Res, 2009 Sep;78(2):230-4.
    PMID: 19481100 DOI: 10.1016/j.mvr.2009.05.005
    Post occlusive skin reactive hyperemia (PORH) is a tool used to assess microcirculation. Endothelial nitric oxide synthase (eNOS) mediates nitric oxide (NO) production; polymorphism of the eNOS gene may affect response to the PORH process. This study aims to determine whether eNOS G894T gene polymorphism affects response to skin PORH. 230 normotensive male and females between 18 and 40 years participated in this cross-sectional study. 170 subjects were of the homozygous GG genotype, whereas 60 were of the GT genotype. Skin PORH was performed by occlusion of the upper arm at 200 mm Hg for 3 min. Skin perfusion and temperature were monitored before, during and after occlusion release using the laser Doppler fluximetry. There were no significant differences between genotypes in their baseline blood pressure, serum cholesterol, BMI and age. Maximum change in perfusion after occlusion release (PORHmax) for the GG and GT genotypes were not significantly different at 50.15+/-1.29 vs. 47.92+/-2.17 AU; ANCOVA, p=0.351. Peak perfusion (PORHpeak) were also not significantly different between the two genotypes (61.23+/-1.36 vs. 57.72+/-2.32 AU; p=0.169). Minimum baseline perfusion were however higher in the GG compared to the GT genotype (10.83+/-0.29 vs. 9.61+/-0.50, p=0.029). We conclude that microvascular reactivity, assessed by change in perfusion after temporary ischemia was not significantly different between the GG and GT genotypes of the eNOS G894T gene. eNOS 894T allele carriers however, have lower baseline perfusion compared to the homozygous G894 allele carrier.
    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
  5. Ghazali DM, Rehman A, Abdul Rahman AR
    Clin Chim Acta, 2008 Feb;388(1-2):46-50.
    PMID: 17977523 DOI: 10.1016/j.cca.2007.10.002
    BACKGROUND: Knowledge of candidate gene polymorphisms in a population is useful for a variety of gene-disease association studies, particularly for some complex traits. A single nucleotide variant of the angiotensinogene gene (AGT M235T) and endothelial nitric oxide synthase gene (eNOS G894T) have been associated with hypertension.
    METHOD: A cross-sectional study consisting of 200 hypertensives and 198 age- and sex-matched controls was conducted. Subjects involved in this study were pure Malay for 3 generations. The AGT M235T and eNOS G894T polymorphisms were determined by PCR-RFLP method.
    RESULTS: The distribution of M235T genotype in the population was 3.5% for MM, 30.4% for MT and 66.1% for TT. No significant difference was observed in genotype (chi(2)=1.30, p=0.52) and allele (chi(2)=0.87, p=0.35) frequencies among the 2 study group. In contrast, the distribution of genotypes for G894T was 74.1% for GG, 24.6% for GT and 1.3% for TT, respectively. Similarly, no significant difference was observed in genotype (chi(2)=0.94, p=0.33) and allele (chi(2)=0.60, p=0.44) frequencies between both study groups.
    CONCLUSION: The AGT M235T and eNOS G894T polymorphisms are unlikely to play an important role in the pathogenesis of hypertension in Malays.
    Study site: Outpatient clinic, Hospital Universiti Sains Malaysia (HUSM); government clinics, Kelantan, Malaysia.
    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics
  6. Chu WC, Aziz AF, Nordin AJ, Cheah YK
    Clin Appl Thromb Hemost, 2016 Sep;22(6):581-8.
    PMID: 25667236 DOI: 10.1177/1076029615571628
    Genetic variants of cholesteryl ester transfer protein (CETP) and endothelial nitric oxide synthase (eNOS) influence high-density lipoprotein cholesterol (HDL-C) metabolism and nitric oxide (NO) synthesis, respectively, and might increase the risk of coronary artery disease (CAD). This study is to investigate the relationship between genetic polymorphisms and the risk of CAD and to evaluate their potential interactions. A total of 237 patients with CAD and 101 controls were genotyped. The association of the polymorphism with the risk of CAD varied among the ethnic groups. Moreover, the concomitant presence of both CETP B1 and eNOS 4a alleles significantly increased the risk of CAD in the Malay group (OR = 33.8, P < .001) and the Indian group (OR = 10.9, P = .031) but not in the Chinese group. This study has identified a novel ethnic-specific gene-gene interaction and suggested that the combination of CETP B1 allele and eNOS 4a allele significantly increases the risk of CAD in Malays and Indians.
    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
  7. Wei LK, Au A, Menon S, Gan SH, Griffiths LR
    J Stroke Cerebrovasc Dis, 2015 Sep;24(9):2017-25.
    PMID: 26187788 DOI: 10.1016/j.jstrokecerebrovasdis.2015.04.011
    The purpose of this study was threefold. First, it was to determine the relationship between serum vitamin profiles and ischemic stroke. The second purpose was to investigate the association of methylenetetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and apolipoprotein-E (ApoE) gene polymorphisms with ischemic stroke and further correlate with serum vitamin profiles among ischemic stroke patients. The third purpose of the study was to highlight the interaction of MTHFR and eNOS haplotypes with serum vitamin profiles and ischemic stroke risks.
    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
  8. Ahmad N, Shah SA, Abdul Gafor AH, Abdul Murad NA, Kamaruddin MA, Abd Jalal N, et al.
    Diabet Med, 2020 11;37(11):1890-1901.
    PMID: 32012348 DOI: 10.1111/dme.14257
    AIM: To examine the possible gene-environment interactions between 32 single nucleotide polymorphisms and environmental factors that could modify the probability of chronic kidney disease.

    METHODS: A case-control study was conducted involving 600 people with type 2 diabetes (300 chronic kidney disease cases, 300 controls) who participated in The Malaysian Cohort project. Retrospective subanalysis was performed on the chronic kidney disease cases to assess chronic kidney disease progression from the recruitment phase. We genotyped 32 single nucleotide polymorphisms using mass spectrometry. The probability of chronic kidney disease and predicted rate of newly detected chronic kidney disease progression were estimated from the significant gene-environment interaction analyses.

    RESULTS: Four single nucleotide polymorphisms (eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895 and KCNQ1 rs2283228) and five environmental factors (age, sex, smoking, waist circumference and HDL) were significantly associated with chronic kidney disease. Gene-environment interaction analyses revealed significant probabilities of chronic kidney disease for sex (PPARGC1A rs8192678), smoking (eNOS rs2070744, PPARGC1A rs8192678 and KCNQ1 rs2237895), waist circumference (eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895 and KCNQ1 rs2283228) and HDL (eNOS rs2070744 and PPARGC1A rs8192678). Subanalysis indicated that the rate of newly detected chronic kidney disease progression was 133 cases per 1000 person-years (95% CI: 115, 153), with a mean follow-up period of 4.78 (SD 0.73) years. There was a significant predicted rate of newly detected chronic kidney disease progression in gene-environment interactions between KCNQ1 rs2283228 and two environmental factors (sex and BMI).

    CONCLUSIONS: Our findings suggest that the gene-environment interactions of eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895 and KCNQ1 rs2283228 with specific environmental factors could modify the probability for chronic kidney disease.

    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*
  9. Jafri AJA, Agarwal R, Iezhitsa I, Agarwal P, Spasov A, Ozerov A, et al.
    Mol Vis, 2018;24:495-508.
    PMID: 30090013
    Purpose: Retinal nitrosative stress associated with altered expression of nitric oxide synthases (NOS) plays an important role in excitotoxic retinal ganglion cell loss in glaucoma. The present study evaluated the effects of magnesium acetyltaurate (MgAT) on changes induced by N-methyl-D-aspartate (NMDA) in the retinal expression of three NOS isoforms, retinal 3-nitrotyrosine (3-NT) levels, and the extent of retinal cell apoptosis in rats. Effects of MgAT with taurine (TAU) alone were compared to understand the benefits of a combined salt of Mg and TAU.

    Methods: Excitotoxic retinal injury was induced with intravitreal injection of NMDA in Sprague-Dawley rats. All treatments were given as pre-, co-, and post-treatment with NMDA. Seven days post-injection, the retinas were processed for measurement of the expression of NOS isoforms using immunostaining and enzyme-linked immunosorbent assay (ELISA), retinal 3-NT content using ELISA, retinal histopathological changes using hematoxylin and eosin (H&E) staining, and retinal cell apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining.

    Results: As observed on immunohistochemistry, the treatment with NMDA caused a 4.53-fold increase in retinal nNOS expression compared to the PBS-treated rats (p<0.001). Among the MgAT-treated groups, only the pretreatment group showed significantly lower nNOS expression than the NMDA-treated group with a 2.00-fold reduction (p<0.001). Among the TAU-treated groups, the pre- and cotreatment groups showed 1.84- and 1.71-fold reduction in nNOS expression compared to the NMDA-treated group (p<0.001), respectively, but remained higher compared to the PBS-treated group (p<0.01). Similarly, iNOS expression in the NMDA-treated group was significantly greater than that for the PBS-treated group (2.68-fold; p<0.001). All MgAT treatment groups showed significantly lower iNOS expression than the NMDA-treated groups (3.58-, 1.51-, and 1.65-folds, respectively). However, in the MgAT co- and post-treatment groups, iNOS expression was significantly greater than in the PBS-treated group (1.77- and 1.62-folds, respectively). Pretreatment with MgAT caused 1.77-fold lower iNOS expression compared to pretreatment with TAU (p<0.05). In contrast, eNOS expression was 1.63-fold higher in the PBS-treated group than in the NMDA-treated group (p<0.001). Among all treatment groups, only pretreatment with MgAT caused restoration of retinal eNOS expression with a 1.39-fold difference from the NMDA-treated group (p<0.05). eNOS expression in the MgAT pretreatment group was also 1.34-fold higher than in the TAU pretreatment group (p<0.05). The retinal NOS expression as measured with ELISA was in accordance with that estimated with immunohistochemistry. Accordingly, among the MgAT treatment groups, only the pretreated group showed 1.47-fold lower retinal 3-NT than the NMDA-treated group, and the difference was significant (p<0.001). The H&E-stained retinal sections in all treatment groups showed statistically significantly greater numbers of retinal cell nuclei than the NMDA-treated group in the inner retina. However, the ganglion cell layer thickness in the TAU pretreatment group remained 1.23-fold lower than that in the MgAT pretreatment group (p<0.05). In line with this observation, the number of apoptotic cells as observed after TUNEL staining was 1.69-fold higher after pretreatment with TAU compared to pretreatment with MgAT (p<0.01).

    Conclusions: MgAT and TAU, particularly with pretreatment, reduce retinal cell apoptosis by reducing retinal nitrosative stress. Pretreatment with MgAT caused greater improvement in NMDA-induced changes in iNOS and eNOS expression and retinal 3-NT levels than pretreatment with TAU. The greater reduction in retinal nitrosative stress after pretreatment with MgAT was associated with lower retinal cell apoptosis and greater preservation of the ganglion cell layer thickness compared to pretreatment with TAU.

    Matched MeSH terms: Nitric Oxide Synthase Type III/genetics
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