Download PDF
Thromb Haemost 2004; 92(02): 413-418
DOI: 10.1160/TH04-02-0103
Cell Signalling and Vessel Remodelling
Schattauer GmbH

Association of NOS3 gene with metabolic syndrome in hypertensive patients

Maria Luisa Fernandez
1   Servicio de Medicina Interna, Hospital de Valme, Seville, Spain
,
Rocio Ruiz
2   Dpto. de Genómica Estructural, Neocodex, Seville, Spain
,
Maria Angeles Gonzalez
1   Servicio de Medicina Interna, Hospital de Valme, Seville, Spain
,
Reposo Ramirez-Lorca
2   Dpto. de Genómica Estructural, Neocodex, Seville, Spain
,
Carmen Couto
3   Servicio de Hematología, Hospital de Valme, Seville, Spain
,
Antonio Ramos
1   Servicio de Medicina Interna, Hospital de Valme, Seville, Spain
,
Reyes Gutierrez-Tous
3   Servicio de Hematología, Hospital de Valme, Seville, Spain
,
Jose Maria Rivera
1   Servicio de Medicina Interna, Hospital de Valme, Seville, Spain
,
Agustin Ruiz
2   Dpto. de Genómica Estructural, Neocodex, Seville, Spain
,
Luis Miguel Real
2   Dpto. de Genómica Estructural, Neocodex, Seville, Spain
,
Antonio Grilo
1   Servicio de Medicina Interna, Hospital de Valme, Seville, Spain
› Author AffiliationsFinancial support: Neocodex have been partially funded by the Ministerio de Ciencia y Tecnología of Spain (FIT-010000-2002-64, FIT 010000-2003-36 and FIT-010000-2003-89).
Further Information

Publication History

Received 17 February 2004

Accepted after resubmission 14 May 2004

Publication Date:
30 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Recent data from animal models indicate that the eNOS null mice present a phenotype that resemble the human metabolic syndrome (hypertension, insulin resistance and hypertriglyceridemia). In this work, we have studied whether NOS3 gene, previously related to endothelial dysfunction, might have a role in metabolic syndrome susceptibility in hypertensive patients. To carry out the study, we genotyped 105 hypertensive patients ≤ 60 years old with two polymorphisms of NOS3 gene: 1132 T>C and 7164 G>T (GeneBank:AF519768.1).To check the allelic frequency of these polymorphisms in our geographical area, we also genotyped 94 unselected healthy controls (control group). To perform sample genotyping, we designed a novel FRET system coupled to real time PCR. There were no differences in genotypic distribution or allelic frequency between hypertensive patients and the control group. However, we observed that 786CC genotype was significantly more frequent in hypertensive patients with metabolic syndrome than in those without the syndrome (p=0.0022). When both polymorphisms were analyzed, we identified the 786C894G as the risk haplotype for metabolic syndrome susceptibility (p=0.011). These data suggest a role of the NOS3 gene in the pathogenesis of metabolic syndrome in hypertensive patients.

Keywords

NOS3 - polymorphism - genetics - metabolic syndrome - hypertension
 

  • References

  • 1 Modan M, Halkin H, Almog S. et al. Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest 1985; 75: 809-817.
    CrossrefPubMedGoogle Scholar
  • 2 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607.
    CrossrefPubMedGoogle Scholar
  • 3 Mykkanen L, Zaccaro DJ, Wagenknecht LE. et al. Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the insulin resistance atherosclerosis study. Diabetes 1998; 47: 793-800.
    CrossrefPubMedGoogle Scholar
  • 4 Bjorntorp P. Fatty acids, hyperinsulinemia, and insulin resistance: which comes first?. Curr Opin Lipidol 1994; 05: 166-174.
    CrossrefPubMedGoogle Scholar
  • 5 Yudkin JS. Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent?. Diabetes Care 1999; 22 (Suppl. 03) C25-30.
    PubMedGoogle Scholar
  • 6 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497.
    CrossrefPubMedGoogle Scholar
  • 7 Freeman MS, Mansfield MW, Barrett JH. et al. Insulin resistance: an atherothrombotic syndrome. The Leeds family study. Thromb Haemost 2003; 89: 161-168.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356-359.
    CrossrefPubMedGoogle Scholar
  • 9 Meigs JB. Epidemiology of the metabolic syndrome. Am J Manag Care 2002; 08: S283-92.
    PubMedGoogle Scholar
  • 10 Kovacs P, van den Brandt J, Kloting I. Genetic dissection of the syndrome X in the rat. Biochem Biophys Res Commun 2000; 269: 660-665.
    CrossrefPubMedGoogle Scholar
  • 11 Lee YJ, Tsai JC. ACE gene insertion/deletion polymorphism associated with 1998 World Health Organization definition of metabolic syndrome in Chinese type 2 diabetic patients. Diabetes Care 25: 1002-1008.
    PubMedGoogle Scholar
  • 12 Tang W, Miller MB, Rich SS. et al. Linkage analysis of a composite factor for the multiple metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study. Diabetes 2003; 52: 2840-2847.
    CrossrefPubMedGoogle Scholar
  • 13 Dallongeville J, Helbecque N, Cottel D. et al. The Gly16—>Arg16 and Gln27—>Glu27 polymorphisms of beta2-adrenergic receptor are associated with metabolic syndrome in men. J Clin Endocrinol Metab 2003; 88: 4862-4866.
    CrossrefPubMedGoogle Scholar
  • 14 Duplain H, Burcelin R, Sartori C. et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001; 104: 342-345.
    CrossrefPubMedGoogle Scholar
  • 15 Lloyd-Jones DM, Bloch KD. The vascular biology of nitric oxide and its role in atherogenesis. Annu Rev Med 1996; 47: 365-375.
    CrossrefPubMedGoogle Scholar
  • 16 Radomski MW, Moncada S. Regulation of vascular homeostasis by nitric oxide. Thromb Haemost 1993; 70: 36-41.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Huang PL, Huang Z, Mashimo H. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377: 239-242.
    CrossrefPubMedGoogle Scholar
  • 18 Forte P, Copland M, Smith LM. et al. Basal nitric oxide synthesis in essential hypertension. Lancet 1997; 349: 837-842.
    CrossrefPubMedGoogle Scholar
  • 19 Miyamoto Y, Saito Y, Kajiyama N. et al. 1998 Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension 1998; 32: 3-8.
    CrossrefPubMedGoogle Scholar
  • 20 Hyndman ME, Parsons HG, Verma S. et al. The T-786—>C mutation in endothelial nitric oxide synthase is associated with hypertension. Hypertension 2002; 39: 919-922.
    CrossrefPubMedGoogle Scholar
  • 21 Kato N, Sugiyama T, Morita H. et al. Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension. Hypertension 1999; 33: 933-936.
    CrossrefPubMedGoogle Scholar
  • 22 Tsujita Y, Baba S, Yamauchi R. et al. Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: The Suita Study. J Hypertens 2001; 19: 1941-1948.
    CrossrefPubMedGoogle Scholar
  • 23 Ohtoshi K, Yamasaki Y, Gorogawa S. et al. Association of (-)786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance. Diabetologia 2002; 45: 1594-1601.
    CrossrefPubMedGoogle Scholar
  • 24 Yoshimura T, Hisatomi A, Kajihara S. et al. The relationship between insulin resistance and polymorphisms of the endothelial nitric oxide synthase gene in patients with coronary artery disease. J Atheroscler Thromb 2003; 10: 43-47.
    CrossrefPubMedGoogle Scholar
  • 25 Monti LD, Barlassina C, Citterio L. et al. Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes 2003; 52: 1270-1275.
    CrossrefPubMedGoogle Scholar
  • 26 Benjafield AV, Morris BJ. Association analyses of endothelial nitric oxide synthase gene polymorphisms in essential hypertension. Am J Hypertens 2000; 13: 994-998.
    CrossrefPubMedGoogle Scholar
  • 27 Ukkola O, Erkkila PH, Savolainen MJ. et al. 2001 Lack of association between polymorphisms of catalase, copper-zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus. J Intern Med 2001; 249: 451-459.
    CrossrefPubMedGoogle Scholar
  • 28 Meigs JB. Epidemiology of cardiovascular complications in type 2 diabetes mellitus. Acta Diabetol 2003; 40 (Suppl. 02) S358-61.
    CrossrefPubMedGoogle Scholar
  • 29 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 (Suppl. 01) S5-20.
    CrossrefPubMedGoogle Scholar
  • 30 Allain CC, Poon LS, Chan CS. et al. Enzymatic determination of total serum cholesterol. Clin Chem 1974; 20: 470-475.
    PubMedGoogle Scholar
  • 31 Friedelwald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
    PubMedGoogle Scholar
  • 32 Real LM, Gayoso AJ, Olivera M. et al. Detection of nucleotide c985 A—>G mutation of medium-chain acyl-CoA dehydrogenase gene by real-time PCR. Clin Chem 2001; 47: 958-959.
    PubMedGoogle Scholar
  • 33 Sasieni PD. From Genotypes to Genes: Doubling the Sample Size. Biometrics 1997; 53: 1253-1261.
    CrossrefPubMedGoogle Scholar
  • 34 Banegas JR, Rodriguez-Artalejo F, de la Cruz, Troca JJ. et al. Blood pressure in Spain: distribution, awareness, control, and benefits of a reduction in average pressure. Hypertension 1998; 32: 998-1002.
    CrossrefPubMedGoogle Scholar
  • 35 Tamayo-Marco B, Faure-Nogueras E, Roche-Asensio MJ. et al. Prevalence of diabetes and impaired glucose tolerance in Aragon, Spain. Diabetes Care 1997; 20: 534-536.
    CrossrefPubMedGoogle Scholar
  • 36 Nakayama M, Yasue H, Yoshimura M. et al. T- 786—>C mutation in the 5’-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999; 99: 2864-2870.
    CrossrefPubMedGoogle Scholar
  • 37 Tesauro M, Thompson WC, Rogliani P. et al. 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 U S A 2000; 97: 2832-2835.
    CrossrefPubMedGoogle Scholar
  • 38 Song J, Yoon Y, Park KU. et al. Genotypespecific influence on nitric oxide synthase gene expression, protein concentrations, and enzyme activity in cultured human endothelial cells. Clin Chem 2003; 49: 847-852.
    CrossrefPubMedGoogle Scholar
  • 39 Rossi GP, Taddei S, Virdis A. et al. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 2003; 41: 938-945.
    CrossrefPubMedGoogle Scholar
  • 40 Cook S, Scherrer U. Insulin resistance, a new target for nitric oxide-delivery drugs. Fundam Clin Pharmacol 2002; 16: 441-453.
    CrossrefPubMedGoogle Scholar