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Endothelial Nitric Oxide Synthase Gene Polymorphisms (− 922A > G, − 786 T > C, Intron 4 b/a VNTR and 894 G > T) and Essential Hypertension: An Association Study with Haplotypes Analysis

Biochemical Genetics volume 58, pages 518–532 (2020)Cite this article

Abstract

Endothelial Nitric Oxide Synthase (eNOS) is an indispensable regulator of blood pressure through producing Nitric Oxide (NO). There is some evidence to suggest that eNOS gene polymorphisms are associated with Essential Hypertension (EHT). In this study, the potential association between eNOS 4a/4b, A922G, G894T, T786C gene polymorphisms and EHT as individual risk factors and as haplotypes are examined in the southern population of Iran (Bandar-Abbas). In this study, 200 EHT patients and 200 normotensive subjects which were matched for age and sex were included. Genotyping was performed by either utilizing Polymerase Chain Reaction (PCR) or PCR followed by Restriction Fragment length Polymorphism (RFLP) method. Our results demonstrated statistically significant associations between T786C, G894T, and 4a/4a and EHT (p < 0.05); however, A922G had no significant association with EHT (p > 0.05). Haplotype analysis also suggested that − 786C/− 922A/4a, − 786C/− 922A/4b and − 786C/− 922G/4a haplotypes were more frequent in EHT group than control group, hypothesizing a positive association with EHT. The present study has identified that the eNOS genetic variations are associated with EHT in southern population of Iran (Bandar-Abbas). These findings also suggested that a number of haplotypes of eNOS gene may be a driving factor for EHT susceptibility in respected population.

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References

  • Benjafield AV, Morris BJ (2000) Association analyses of endothelial nitric oxide synthase gene polymorphisms in essential hypertension. Am J Hypertens 13(9):994–998

    CAS  PubMed  Google Scholar 

  • Cardon LR, Abecasis GR (2003) Using haplotype blocks to map human complex trait loci. Trends Genet 19(3):135–140

    CAS  PubMed  Google Scholar 

  • Chandra S, Narang R, Sreenivas V, Bhatia J, Saluja D, Srivastava K (2014) Association of angiotensin II type 1 receptor (A1166C) gene polymorphism and its increased expression in essential hypertension: a case–control study. PLoS ONE ONE 9(7):e101502

    Google Scholar 

  • Colomba D, Duro G, Corrao S, Argano C, Di Chiara T, Nuzzo D et al (2008) Endothelial nitric oxide synthase gene polymorphisms and cardiovascular damage in hypertensive subjects: an Italian case–control study. Immun Ageing 5(1):4

    PubMed  PubMed Central  Google Scholar 

  • Cooke M, John P, Dzau M, Victor J (1997) Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 48(1):489–509

    CAS  PubMed  Google Scholar 

  • Deng F, Hu Q, Tang B, He F, Guo S, Chen J et al (2007) Endothelial nitric oxide synthase gene intron 4, 27 bp repeat polymorphism and essential hypertension in the Kazakh Chinese population. Acta Biochim Biophys Sin 39(5):311–316

    CAS  PubMed  Google Scholar 

  • Gamboa A, Shibao C, Diedrich A, Choi L, Pohar B, Jordan J et al (2007) Contribution of endothelial nitric oxide to blood pressure in humans. Hypertension 49(1):170–177

    CAS  PubMed  Google Scholar 

  • Hingorani AD (2001) Polymorphisms in endothelial nitric oxide synthase and atherogenesis. Atherosclerosis 154(3):521–527

    CAS  PubMed  Google Scholar 

  • Hyndman ME, Parsons HG, Verma S, Bridge PJ, Edworthy S, Jones C et al (2002) The T-786→C mutation in endothelial nitric oxide synthase is associated with hypertension. Hypertension 39(4):919–922

    CAS  PubMed  Google Scholar 

  • Jemaa R, Ali SB, Kallel A, Feki M, Elasmi M, Taieb SH et al (2009) Association of a 27-bp repeat polymorphism in intron 4 of endothelial constitutive nitric oxide synthase gene with hypertension in a Tunisian population. Clin Biochem 42(9):852–856

    CAS  PubMed  Google Scholar 

  • Jemaa R, Kallel A, Sediri Y, Omar S, Feki M, Elasmi M et al (2011) Association between-786TC polymorphism in the endothelial nitric oxide synthase gene and hypertension in the Tunisian population. Exp Mol Pathol 90(2):210–214

    CAS  PubMed  Google Scholar 

  • Jíra M, Závodná E, Honzíková N, Nováková Z, Vasku A, Hollá LI et al (2011) Association of eNOS gene polymorphisms T-786C and G894T with blood pressure variability in man. Physiol Res 60(1):193

    PubMed  Google Scholar 

  • Kajiyama N, Saito Y, Miyamoto Y, Yoshimura M, Nakayama M, Harada M et al (2000) Lack of association between T-786→ C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene and essential hypertension. Hypertens Res 23(6):561–565

    CAS  PubMed  Google Scholar 

  • Kato N, Sugiyama T, Morita H, Nabika T, Kurihara H, Yamori Y et al (1999) Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension. Hypertension 33(4):933–936

    CAS  PubMed  Google Scholar 

  • Kingah PL, Luu HN, Volcik KA, Morrison AC, Nettleton JA, Boerwinkle E (2010) Association of NOS3 Glu298Asp SNP with hypertension and possible effect modification of dietary fat intake in the ARIC study. Hypertens Res 33(2):165–169

    CAS  PubMed  Google Scholar 

  • Kishimoto T, Misawa Y, Kaetu A, Nagai M, Osaki Y, Okamoto M et al (2004) eNOS Glu298Asp polymorphism and hypertension in a cohort study in Japanese. Prev Med 39(5):927–931

    CAS  PubMed  Google Scholar 

  • Kitsios GD, Zintzaras E (2010) An NOS3 haplotype is protective against hypertension in a Caucasian population. Int J Hypertens 2010:865031

    PubMed  PubMed Central  Google Scholar 

  • Kumar R, Nejatizadeh A, Arif E, Akhtar S, Gupta M, Tyagi S et al (2009) Multi-locus interactions of vascular homeostasis genes in essential hypertension: a gender-based study. Clin Chim Acta 405(1):87–93

    CAS  PubMed  Google Scholar 

  • Lacolley P, Gautier S, Poirier O, Pannier B, Cambien F, Benetos A (1998) Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects. J Hypertens 16(1):31–35

    CAS  PubMed  Google Scholar 

  • Li R, Lyn D, Lapu-Bula R, Oduwole A, Igho-Pemu P, Lankford B et al (2004) Relation of endothelial nitric oxide synthase gene to plasma nitric oxide level, endothelial function, and blood pressure in African Americans. Am J Hypertens 17(7):560–567

    CAS  PubMed  Google Scholar 

  • Li A, Song B, Zheng H, Zhang X, He Y, Xu Y (2007) Association between the variable number of tandem repeat polymorphisms of endothelial nitric oxide synthase and ischemic cerebrovascular diseases in Henan Han ethnicity. Life Sci J 4:26–29

    CAS  Google Scholar 

  • Li J, Cun Y, Tang W, Wang Y, Li S, Ouyang H et al (2011) Association of eNOS gene polymorphisms with essential hypertension in the Han population in southwestern China. Genet Mol Res 10(3):2202–2212

    CAS  PubMed  Google Scholar 

  • Marroni AS, Metzger IF, Souza-Costa DC, Nagassaki S, Sandrim VC, Correa RX et al (2005) Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase genetic polymorphisms. Nitric Oxide 12(3):177–182

    CAS  PubMed  Google Scholar 

  • Men C, Tang K, Lin G, Li J, Zhan Y (2011) ENOS-G894T polymorphism is a risk factor for essential hypertension in China. Indian J Biochem Biophys 48(3):154

    CAS  PubMed  Google Scholar 

  • Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M et al (1998) Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension 32(1):3–8

    CAS  PubMed  Google Scholar 

  • Miyamoto Y, Saito Y, Nakayama M, Shimasaki Y, Yoshimura T, Yoshimura M et al (2000) Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a–786T→ C mutation associated with coronary spastic angina. Hum Mol Genet 9(18):2629–2637

    CAS  PubMed  Google Scholar 

  • Moe K, Lim S, Wong P, Chua T, DeSilva D, Koh T et al (2006) Association analysis of endothelial nitric oxide synthase gene polymorphism with primary hypertension in a Singapore population. J Hum Hypertens 20(12):956

    CAS  PubMed  Google Scholar 

  • Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H et al (1999) T− 786→ C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 99(22):2864–2870

    CAS  PubMed  Google Scholar 

  • Nejatizadeh A, Kumar R, Stobdan T, Goyal A, Sikdar S, Gupta M et al (2008) Endothelial nitric oxide synthase gene haplotypes and circulating nitric oxide levels significantly associate with risk of essential hypertension. Free Radical Biol Med 44(11):1912–1918

    CAS  Google Scholar 

  • Niu W, Qi Y (2011) An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension. PLoS ONE ONE 6(9):e24266

    CAS  Google Scholar 

  • Rahimi Z, Aghaei A, Rahimi Z, Vaisi-Raygani A (2013) Endothelial nitric oxide synthase (eNOS) 4a/b and G894T polymorphisms and susceptibility to preeclampsia. J Reprod Infertil 14(4):184

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rios DL, D’Onofrio LO, Souza JK, Queiroz AM, Raduy-Maron L, Silva-Neto N et al (2007) Smoking-dependent and haplotype-specific effects of endothelial nitric oxide synthase gene polymorphisms on angiographically assessed coronary artery disease in Caucasian-and African–Brazilians. Atherosclerosis 193(1):135–141

    CAS  PubMed  Google Scholar 

  • Rodrigo R, Libuy M, Feliú F, Hasson D (2013) Oxidative stress-related biomarkers in essential hypertension and ischemia-reperfusion myocardial damage. Dis Markers 35(6):773–790

    PubMed  PubMed Central  Google Scholar 

  • Salvi E, Kutalik Z, Glorioso N, Benaglio P, Frau F, Kuznetsova T et al (2012) Genome-wide association study using a high-density SNP-array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of eNOS. Hypertension 59(2):248

    CAS  PubMed  Google Scholar 

  • Sandrim VC, Coelho EB, Nobre F, Arado GM, Lanchote VL, Tanus-Santos JE (2006a) Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis 186(2):428–432

    CAS  PubMed  Google Scholar 

  • Sandrim VC, Yugar-Toledo JC, Desta Z, Flockhart DA, Moreno H Jr, Tanos-Santos JE (2006b) Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy. J Hypertens 24(12):2393–2397

    CAS  PubMed  Google Scholar 

  • Shah V, Cheema B, Kohli H, Sharma R, Khullar M, Bhansali A (2013) Endothelial nitric oxide synthase gene polymorphism and the risk of diabetic neuropathy in asian indian patients with type 2 diabetes. J Diabetes Metab 4(2):243

    Google Scholar 

  • Shankarishan P, Borah PK, Ahmed G, Mahanta J (2014) Endothelial nitric oxide synthase gene polymorphisms and the risk of hypertension in an Indian population. BioMed Res Int 2014:793040

    PubMed  PubMed Central  Google Scholar 

  • Shoji M, Tsutaya S, Saito R, Takamatu H, Yasujima M (2000) Positive association of endothelial nitric oxide synthase gene polymorphism with hypertension in northern Japan. Life Sci 66(26):2557–2562

    CAS  PubMed  Google Scholar 

  • Tanus-Santos JE, Desai M, Flockhart DA (2001) Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenet Genomics 11(8):719–725

    Google Scholar 

  • Tsujita Y, Baba S, Yamauchi R, Mannami T, Kinoshita M, Yamamoto R et al (2001) Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: the Suita Study. J Hypertens 19(11):1941–1948

    CAS  PubMed  Google Scholar 

  • Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A et al (1998) Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun 245(1):190–193

    CAS  PubMed  Google Scholar 

  • Wang XL, Sim AS, Badenhop RF, Mccredie RM, Wilcken DE (1996) A smoking–dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat Med 2(1):41–45

    CAS  PubMed  Google Scholar 

  • Yoshimura M, Yasue H, Nakayama M, Shimasaki Y, Sumida H, Sugiyama S et al (1998) A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese. Hum Genet 103(1):65–69

    CAS  PubMed  Google Scholar 

  • Zarmakhi L, Hashemi M (2012) The analysis of endothelial nitric oxide synthase gene polymorphism in intron 4 with hypertension disease. J Paramed Sci 3(1):2–6

    Google Scholar 

  • Zintzaras E, Kitsios G, Stefanidis I (2007) Response to endothelial nitric oxide synthase polymorphisms and susceptibility to hypertension: genotype versus haplotype analysis. Hypertension 49(1):E2

    CAS  Google Scholar 

  • Zintzaras E, Lau J (2008) Synthesis of genetic association studies for pertinent gene–disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol 61(7):634–645

    PubMed  Google Scholar 

  • Zintzaras E, Kitsios G, Stefanidis I (2006) Endothelial NO synthase gene polymorphisms and hypertension. Hypertension 48(4):700–710

    CAS  PubMed  Google Scholar 

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Acknowledgments

Authors would like to express their sincerest appreciation to all subjects for participating in this study.

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Affiliations

  1. Molecular Medicine Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Zahra Farbood, Amirsaeed Sabeti Aghabozorgi, Azim Nejatizadeh, Leila Shams, Elahe Mansouri Babamansouri & Mohammad Shekari

  2. Hormozgan Cardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Hossein Farshidi

  3. Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada

    Amirhossein Bahreyni

  4. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    Amirhossein Bahreyni

Authors
  1. Zahra Farbood
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  2. Amirsaeed Sabeti Aghabozorgi
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  3. Azim Nejatizadeh
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  4. Hossein Farshidi
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  5. Leila Shams
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  6. Amirhossein Bahreyni
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  7. Elahe Mansouri Babamansouri
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  8. Mohammad Shekari
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Correspondence to Mohammad Shekari.

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Farbood, Z., Sabeti Aghabozorgi, A., Nejatizadeh, A. et al. Endothelial Nitric Oxide Synthase Gene Polymorphisms (− 922A > G, − 786 T > C, Intron 4 b/a VNTR and 894 G > T) and Essential Hypertension: An Association Study with Haplotypes Analysis. Biochem Genet 58, 518–532 (2020). https://doi.org/10.1007/s10528-020-09953-2

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Keywords

  • eNOS polymorphism
  • − 922A/G
  • − 786 t/c
  • Intron 4 b/a VNTR
  • 894 g/t
  • Haplotype
  • Essential hypertension