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      Molecular Analysis of rs2070744 and rs1799983 Polymorphisms of NOS3 Gene in Iranian Patients With Multiple Sclerosis

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          Abstract

          Introduction:

          Multiple Sclerosis (MS) is a disease of central nervous system that mainly causes lesions or plaques in the spinal cord and brain. The purpose of this study was to analyze the relation between c.-813C>T (rs2070744) and c.894G>T (rs1799983) polymorphisms of NOS3 gene and MS in Iranian patients.

          Methods:

          A total of 78 patients with MS and 80 healthy controls were screened for NOS3 (rs2070744 and rs1799983) Single Nucleotide Polymorphisms (SNPs) by tetra-primer multiplex ARMS-PCR and PCR-RFLP.

          Results:

          Genotype frequencies of the c.-813C>T polymorphism in patients compared to controls were as follows: 53.8% to 80.0% for TT genotype, 41.0% to 18.8% for TC genotype, and 5.1% versus 1.2% for CC genotype (P=0.001). The frequencies of GG genotype was 57.7% and 78.8% and for GT genotype of c.894G>T polymorphism in patients compared to control subjects was 42.3% and 21.2%, respectively (P=0.004).

          Conclusion:

          Our results indicate that the studied NOS3 polymorphisms may be associated with MS in Iranian patients.

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          Most cited references21

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          Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review.

          Liam Smeeth, Juan Casas, Aroon D Hingorani … (2006)
          This review examines the association of a subset of endothelial nitric oxide synthase gene (NOS3) polymorphisms (Glu298Asp, intron 4, and -786T>C) with cardiovascular disease. The Glu298Asp polymorphism within exon 7 is the only common nonsynonymous variant. The variants have been associated with low plasma nitric oxide concentrations and reduced vascular reactivity; difficulties in measuring those phenotypes means that their functional role remains unclear. A large meta-analysis of NOS3 polymorphisms in coronary heart disease revealed per-allele odds ratios of 1.17 (95% confidence interval: 1.07, 1.28) for Glu298Asp, 1.17 (95% confidence interval: 1.07, 1.28) for -786T>C, and 1.12 (95% confidence interval: 1.01, 1.24) for intron 4. However, there was evidence that small studies with more striking results could affect the associations of the Glu298Asp and -786T>C polymorphisms with coronary heart disease. Associations of NOS3 polymorphisms with hypertension, preeclampsia, stroke, and diabetes remain uncertain. To date, no reliable gene-gene or gene-environmental interactions have been described. Use of these variants in predictive testing is unlikely to be useful, although the population attributable fraction could be substantial if the modest associations are causal. The need for large-scale genetic association studies using tagging polymorphisms is warranted to confirm or refute a role of the NOS3 gene in coronary heart disease.
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            The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide.

            Bart A J Veldman, Wilko Spiering, Peter A. Doevendans … (2002)
            The endothelial nitric oxide synthase Glu298Asp polymorphism has been suggested to play a role in the development of hypertension, atherosclerosis and coronary artery disease. To investigate functional differences between the various genotypes with respect to basal nitric oxide (NO) production, we estimated the response to endothelial NO synthase (ecNOS) inhibition by infusion of increasing doses of N(G)-monomethyl-L-arginine (L-NMMA) into the brachial artery during venous occlusion plethysmography. In 41 healthy subjects forearm blood flow responses to intra-arterial infusion of increasing doses of L-NMMA (0.05, 0.1 and 0.2 mg/min per dl) and norepinephrine (10, 20 and 40 ng/min per dl) were measured. The genotype of the ecNOS Glu298Asp polymorphism was assessed. Nineteen subjects had the Glu/Glu genotype, 19 subjects had the Glu/Asp genotype and three subjects had the Asp/Asp genotype. Groups were comparable concerning demographic, hemodynamic and possible confounding factors. Subjects with the Asp allele showed a reduced response to infusion of L-NMMA as compared to subjects with the Glu/Glu genotype (ANOVA, = 0.01). There was no significant difference in the response to infusion of the NO-independent vasoconstrictor, norepinephrine, between both groups. The ecNOS Glu298Asp polymorphism is associated with reduced basal NO production and might therefore have functional implications in the development of atherosclerosis or hypertension.
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              Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels.

              L. Almasy, T. Wang, David Wilcken … (1997)
              Nitric oxide (NO) has an important physiological role in regulating vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial constitutive nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO production. We used a combination of maximum-likelihood-based statistical genetic methods to explore the contributions of the ecNOS gene and other unmeasured genes to basal NO production measured by its metabolites (NOx: nitrite and nitrate) in 428 members of 108 nuclear families. Our initial quantitative genetic analysis estimated that approximately 30% of the variance in fasting NOx levels is due to genes (chi 2(1) = 16.04, P = .000062). Complex segregation analysis detected the effects of both a single locus and residual polygenes on NOx levels, and measured genotype analysis showed that plasma NOx levels in those homozygous for the rare allele (64.9 +/- 7.8 mumol/L) were significantly higher (P = .000242) than those homozygous for the common allele (30.2 +/- 3.1 mumol/L). The results of the variance component linkage analysis were consistent with linkage of a quantitative trait locus in or near the ecNOS gene to variation in plasma NOx levels (P = .0066). While many environmental factors have been shown to alter transiently plasma NOx levels, our study is the first to identify a substantial effect of the ecNOS locus on the variance of plasma NOx, i.e. basal NO production. This finding may be relevant to atherogenesis and NO-related disorders.
              Article 0 comments Cited 30 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Basic Clin Neurosci
                Journal ID (iso-abbrev): Basic Clin Neurosci
                Journal ID (publisher-id): BCN
                Journal ID (pmc): BCN
                Title: Basic and Clinical Neuroscience
                Publisher: Iranian Neuroscience Society
                ISSN (Print): 2008-126X
                ISSN (Electronic): 2228-7442
                Publication date (Print): Jul-Aug 2017
                Volume: 8
                Issue: 4
                Pages: 279-284
                Affiliations
                [1. ]Department of Biology, Faculty of Science, Yazd University, Yazd, Iran.
                [2. ]Department of Biology, Ashkezar Branch, Islamic Azad University, Yazd, Iran.
                Author notes
                [* ]Corresponding Author: Mohammad Mehdi Heidari, PhD, Address: Department of Biology, Faculty of Science, Yazd University, Yazd, Iran. Tel:+98 (35) 31233381, E-mail: Heidarimm@ 123456yazd.ac.ir
                Article
                Publisher ID: bcn-8-279
                DOI: 10.18869/nirp.bcn.8.4.279
                PMC ID: 5683685
                PubMed ID: 29158878
                SO-VID: 46707ad8-0228-419d-8de4-b5db512cef25
                Copyright © Copyright© 2017 Iranian Neuroscience Society
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 13 December 2016
                Date revision received : 12 January 2017
                Date accepted : 05 May 2017
                Categories
                Subject: Research Paper

                Keywords: multiple sclerosis,nos3 gene,rs2070744,rs1799983,polymorphism
                Data availability:
                Keywords: multiple sclerosis, nos3 gene, rs2070744, rs1799983, polymorphism

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