Skip to main content

Influence of fat intake and BMI on the association of rs1799983 NOS3 polymorphism with blood pressure levels in an Iberian population

European Journal of Nutrition volume 56, pages 1589–1596 (2017)Cite this article

Abstract

Purpose

There is controversy about the effect of the rs1799983 nitric oxide synthase (NOS3) genetic variant on hypertension and blood pressure (BP) levels. The aims of the current study were to examine whether rs1799983 affects BP levels and to identify potential interactions between this polymorphism and other non-genetic risk factors.

Methods

A total of 705 subjects were examined for anthropometric and body composition measurements, BP, dietary habits and physical activity. Oral epithelial cells were collected for the identification of rs1799983 using Luminex® 100/200TM System.

Results

After adjusted for covariates, TT genotype showed a 2.30-fold higher predisposition of hypertension than GG genotype subjects. According to BP levels, for each risk allele diastolic blood pressure (DBP) increased in 1.99 mmHg. Significant interactions between rs1799983 and saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) were found. Moreover, an interaction with body weight status was observed. Among overweight individuals, T allele carriers showed higher DBP than GG genotype.

Conclusion

The present study evidenced that rs1799983 NOS3 polymorphism could be associated with hypertension and DBP among Southern Europeans, being this association influenced by dietary fat (SFA and MUFA) and body mass index.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. World Health Organization (WHO) (2013) A global brief on hypertension. World Health Organization, Geneva

    Google Scholar 

  2. Lim SS, Vos T, Flaxman AD et al (2012) A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2224–2260

    Article  Google Scholar 

  3. Zhao Q, Kelly TN, Li C, He J (2013) Progress and future aspects in genetics of human hypertension. Curr Hypertens Rep 15:676–686

    CAS  Article  Google Scholar 

  4. Butler MG (2010) Genetics of hypertension. Current status. J Med Liban 58:175–178

    Google Scholar 

  5. Gamboa A, Shibao C, Diedrich A, Choi L, Pohar B, Jordan J, Paranjape S, Farley G, Biaggioni I (2007) Contribution of endothelial nitric oxide to blood pressure in humans. Hypertension 49:170–177

    CAS  Article  Google Scholar 

  6. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377:239–242

    CAS  Article  Google Scholar 

  7. Vecoli C (2014) Endothelial nitric oxide synthase gene polymorphisms in cardiovascular disease. Vitam Horm 96:387–406

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  9. Hall WL (2009) Dietary saturated and unsaturated fats as determinants of blood pressure and vascular function. Nutr Res Rev 22:18–38

    CAS  Article  Google Scholar 

  10. DeMarco VG, Aroor AR, Sowers JR (2014) The pathophysiology of hypertension in patients with obesity. Nat Rev Endocrinol 10:364–376

    CAS  Article  Google Scholar 

  11. Abdel-Aziz TA, Mohamed RH (2013) Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease. Mol Biol Rep 40:3065–3071

    CAS  Article  Google Scholar 

  12. Panel on Macronutrients, Panel on the Definition of Dietary Fiber, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (2005) Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (Macronutrients). The National Academies Press, Washington, DC

    Google Scholar 

  13. Grim CE, Grim CM (2009) The Omron Elite 7300 W home blood pressure monitor passes the European Society of Hypertension International Validation Protocol for women and men. Blood Press Monit 14:87–90

    Article  Google Scholar 

  14. Fava C, Sjogren M, Montagnana M, Danese E, Almgren P, Engstrom G, Nilsson P, Hedblad B, Guidi GC, Minuz P, Melander O (2013) Prediction of blood pressure changes over time and incidence of hypertension by a genetic risk score in Swedes. Hypertension 61:319–326

    CAS  Article  Google Scholar 

  15. International Consortium for Blood Pressure Genome-Wide Association Studies, Ehret GB, Munroe PB et al (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103–109

    Article  Google Scholar 

  16. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Kottgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O’Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM (2009) Genome-wide association study of blood pressure and hypertension. Nat Genet 41:677–687

    CAS  Article  Google Scholar 

  17. Newton-Cheh C, Johnson T, Gateva V et al (2009) Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 41:666–676

    CAS  Article  Google Scholar 

  18. Dunbar SA (2006) Applications of Luminex xMAP technology for rapid, high-throughput multiplexed nucleic acid detection. Clin Chim Acta 363:71–82

    CAS  Article  Google Scholar 

  19. Conen D, Cheng S, Steiner LL, Buring JE, Ridker PM, Zee RY (2009) Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: the Women’s Genome Health Study. J Hypertens 27:476–483

    CAS  Article  Google Scholar 

  20. Rai H, Parveen F, Kumar S, Kapoor A, Sinha N (2014) Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review. PLoS ONE 9:e113363

    Article  Google Scholar 

  21. Xin Y, Song X, Xue H, Liu Z, Wang X, Wang H, Sun K, Bai Y, Liu J, Hui R (2009) A common variant of the eNOS gene (E298D) is an independent risk factor for left ventricular hypertrophy in human essential hypertension. Clin Sci (Lond) 117:67–73

    CAS  Article  Google Scholar 

  22. Qin J, Dai J, Xu Z, Chen D, Qin J, Shi D, Teng H, Jiang Q (2013) Genetic polymorphism of NOS3 with susceptibility to deep vein thrombosis after orthopedic surgery: a case-control study in Chinese Han population. PLoS ONE 8:e70033

    CAS  Article  Google Scholar 

  23. Persu A, Stoenoiu MS, Messiaen T, Davila S, Robino C, El-Khattabi O, Mourad M, Horie S, Feron O, Balligand JL, Wattiez R, Pirson Y, Chauveau D, Lens XM, Devuyst O (2002) Modifier effect of ENOS in autosomal dominant polycystic kidney disease. Hum Mol Genet 11:229–241

    CAS  Article  Google Scholar 

  24. Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J (2000) 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 97:2832–2835

    CAS  Article  Google Scholar 

  25. Fairchild TA, Fulton D, Fontana JT, Gratton JP, McCabe TJ, Sessa WC (2001) Acidic hydrolysis as a mechanism for the cleavage of the Glu(298) → Asp variant of human endothelial nitric-oxide synthase. J Biol Chem 276:26674–26679

    CAS  Article  Google Scholar 

  26. McDonald DM, Alp NJ, Channon KM (2004) Functional comparison of the endothelial nitric oxide synthase Glu298Asp polymorphic variants in human endothelial cells. Pharmacogenetics 14:831–839

    CAS  Article  Google Scholar 

  27. Joshi MS, Mineo C, Shaul PW, Bauer JA (2007) Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. FASEB J 21:2655–2663

    CAS  Article  Google Scholar 

  28. Kimura L, Angeli CB, Auricchio MT, Fernandes GR, Pereira AC, Vicente JP, Pereira TV, Mingroni-Netto RC (2012) Multilocus family-based association analysis of seven candidate polymorphisms with essential hypertension in an african-derived semi-isolated brazilian population. Int J Hypertens 2012:859219

    CAS  Article  Google Scholar 

  29. Nunes RA, Barroso LP, Pereira Ada C, Krieger JE, Mansur AJ (2014) Gender-related associations of genetic polymorphisms of alpha-adrenergic receptors, endothelial nitric oxide synthase and bradykinin B2 receptor with treadmill exercise test responses. Open Heart 1:e000132

    Article  Google Scholar 

  30. Seidlerova J, Filipovsky J, Mayer O Jr, Kucerova A, Pesta M (2015) Association between endothelial NO synthase polymorphisms and arterial properties in the general population. Nitric Oxide 44:47–51

    CAS  Article  Google Scholar 

  31. Delgado-Lista J, Garcia-Rios A, Perez-Martinez P, Fuentes F, Jimenez-Gomez Y, Gomez-Luna MJ, Parnell LD, Marin C, Lai CQ, Perez-Jimenez F, Ordovas JM, Lopez-Miranda J (2011) Gene variations of nitric oxide synthase regulate the effects of a saturated fat rich meal on endothelial function. Clin Nutr 30:234–238

    CAS  Article  Google Scholar 

  32. 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 33:165–169

    CAS  Article  Google Scholar 

  33. Pereira TV, Rudnicki M, Cheung BM, Baum L, Yamada Y, Oliveira PS, Pereira AC, Krieger JE (2007) Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias. J Hypertens 25:1763–1774

    CAS  Article  Google Scholar 

  34. Martins MA, Catta-Preta M, Mandarim-de-Lacerda CA, Aguila MB, Brunini TC, Mendes-Ribeiro AC (2010) High fat diets modulate nitric oxide biosynthesis and antioxidant defence in red blood cells from C57BL/6 mice. Arch Biochem Biophys 499:56–61

    CAS  Article  Google Scholar 

  35. Grove ML, Morrison A, Folsom AR, Boerwinkle E, Hoelscher DM, Bray MS (2007) Gene-environment interaction and the GNB3 gene in the Atherosclerosis Risk in Communities study. Int J Obes (Lond) 31:919–926

    CAS  Article  Google Scholar 

  36. Xi B, Zhao X, Chandak GR, Shen Y, Cheng H, Hou D, Wang X, Mi J (2013) Influence of obesity on association between genetic variants identified by genome-wide association studies and hypertension risk in Chinese children. Am J Hypertens 26:990–996

    CAS  Article  Google Scholar 

  37. Marteau JB, Sass C, Pfister M, Lambert D, Noyer-Weidner M, Visvikis S (2004) The Leu554Phe polymorphism in the E-selectin gene is associated with blood pressure in overweight people. J Hypertens 22:305–311

    CAS  Article  Google Scholar 

  38. Silva DA, Petroski EL, Peres MA (2013) Accuracy and measures of association of anthropometric indexes of obesity to identify the presence of hypertension in adults: a population-based study in Southern Brazil. Eur J Nutr 52:237–246

    CAS  Article  Google Scholar 

  39. Hickner RC, Kemeny G, Stallings HW, Manning SM, McIver KL (2006) Relationship between body composition and skeletal muscle eNOS. Int J Obes (Lond) 30:308–312

    CAS  Article  Google Scholar 

  40. Kraus RM, Houmard JA, Kraus WE, Tanner CJ, Pierce JR, Choi MD, Hickner RC (2015) Obesity, insulin resistance, and skeletal muscle nitric oxide synthase. J Appl Physiol (1985) 113:758–765

    Article  Google Scholar 

  41. da Cunha NV, Pinge-Filho P, Panis C, Silva BR, Pernomian L, Grando MD, Cecchini R, Bendhack LM, Martins-Pinge MC (2014) Decreased endothelial nitric oxide, systemic oxidative stress, and increased sympathetic modulation contribute to hypertension in obese rats. Am J Physiol Heart Circ Physiol 306:H1472–H1480

    Article  Google Scholar 

Download references

Acknowledgments

We thank all the seekers of the Nutrigenetic Service who voluntarily offered their data. The authors are grateful to the five nutritionists for data collection and to Amaia Ibañez for excellent technical assistance. The authors thank the Linea Especial (University of Navarra; LE/97) and to the Spanish Ministry of Economy and Competitiveness (AGL2013-45554-R project) for financial support, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)/RETICS schedules (Instituto de Salud Carlos III, Madrid, Spain) for assistance in this study and the support from CINFA (Olloki, Spain) concerning the genetic tools and general logistic. The predoctoral research grant to Leticia Goñi from the Asociación de Amigos Universidad de Navarra is gratefully acknowledged.

Author information

Affiliations

  1. Department of Nutrition, Food Sciences and Physiology, University of Navarra, Irunlarrea, 1, 31008, Pamplona, Navarra, Spain

    Leticia Goni, Marta Cuervo, Fermín I. Milagro & J. Alfredo Martínez

  2. Centre for Nutrition Research, University of Navarra, Pamplona, Spain

    Leticia Goni, Marta Cuervo, Fermín I. Milagro & J. Alfredo Martínez

  3. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain

    Marta Cuervo, Fermín I. Milagro & J. Alfredo Martínez

  4. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    Marta Cuervo & J. Alfredo Martínez

Authors
  1. Leticia Goni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Cuervo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fermín I. Milagro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Alfredo Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Alfredo Martínez.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The Research Ethics Committee of the University of Navarra provided confirmation of fulfillment of the ethical standards affecting this research (Ref. 2410/2014). Therefore, the survey was in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Goni, L., Cuervo, M., Milagro, F.I. et al. Influence of fat intake and BMI on the association of rs1799983 NOS3 polymorphism with blood pressure levels in an Iberian population. Eur J Nutr 56, 1589–1596 (2017). https://doi.org/10.1007/s00394-016-1203-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-016-1203-3

Keywords

  • Hypertension
  • Blood pressure
  • NOS3
  • Saturated fatty acids
  • Monounsaturated fatty acids
  • Obesity