AMI is associated with polymorphisms in the NOS3 and FGB but not in PAI-1 genes in young adults.

BACKGROUND We investigated the relationship between NOS3, FGB and PAI-1 polymorphisms and endothelial dysfunction and risk factors for acute myocardial infarction (AMI) in young adults. METHODS Endothelial function was measured by response to flow mediated vasodilation (FMV) and induced by nitrate (FMN). Biochemical parameters were measured by standard enzymatic methods and plasma total nitrate was analyzed by the NOA system. NOS3 (T-786C, G894T and intron 4A/B STR), FGB (C-148T and G-455A) and PAI-1 (4G/5G) polymorphisms were determined by PCR-RFLP. RESULTS Concentrations of total and LDL cholesterol, apo B, triglycerides, nitrate, PAI-1 and fibrinogen were higher and apo AI, HDL cholesterol and FMV were lower in AMI patients than in controls (p<0.001). PAI-1 (p<0.001) but not nitrate was higher in AMI patients with low response to FMV. NOS3 T-786C and FGB C-148T polymorphisms were associated with AMI (p<0.050). NOS3 T-786C was also related to hypertension (p=0.049). NOS3 intron 4A/B STR was associated with increased concentrations of total cholesterol and apo B. NOS3-786TT/894GT haplotype was associated with increased FMV (p=0.018) than the other haplotypes. CONCLUSIONS Our data suggest NOS3 and FGB polymorphisms are associated with AMI. NOS3 is also related to hypertension, endothelial dysfunction and variation on serum cholesterol in young adults with AMI.

[1]  A. Wu,et al.  Correlation of polymorphisms to coagulation and biochemical risk factors for cardiovascular diseases. , 2001, The American journal of cardiology.

[2]  C. Shin,et al.  Smoking status-dependent association of the 27-bp repeat polymorphism in intron 4 of endothelial nitric oxide synthase gene with plasma nitric oxide concentrations. , 2002, Clinica chimica acta; international journal of clinical chemistry.

[3]  M. Hirata,et al.  Optimized procedure for DNA isolation from fresh and cryopreserved clotted human blood useful in clinical molecular testing. , 1998, Clinical chemistry.

[4]  L. Bernardinelli,et al.  Tissue plasminogen activator antigen is strongly associated with myocardial infarction in young women , 2005, Journal of thrombosis and haemostasis : JTH.

[5]  M. Hirata,et al.  Five polymorphisms in gene candidates for cardiovascular disease in Afro‐Brazilian individuals , 2004, Journal of clinical laboratory analysis.

[6]  M. Roest,et al.  The 4G‐allele of the PAI‐1 gene is not consistently associated with a higher prevalence of coronary stenosis , 2004, Journal of thrombosis and haemostasis : JTH.

[7]  M. Hirata,et al.  A Method to Detect the G894T Polymorphism of the NOS3 Gene. Clinical Validation in Familial Hypercholesterolemia , 2002, Clinical chemistry and laboratory medicine.

[8]  J. Coresh,et al.  Beta-fibrinogen haplotypes and the risk for cardiovascular disease in a dialysis cohort. , 2005, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[9]  S. Thompson,et al.  Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. , 1995, The New England journal of medicine.

[10]  P. Reitsma,et al.  The 4G/5G Polymorphism in the Plasminogen Activator Inhibitor-1 Gene Is not Associated with Myocardial Infarction , 1999, Thrombosis and Haemostasis.

[11]  S. Thompson,et al.  Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. , 1996, Circulation.

[12]  B Neal,et al.  1999 World Health Organization-International Society of Hypertension Guidelines for the management of hypertension. Guidelines sub-committee of the World Health Organization. , 1999, Clinical and experimental hypertension.

[13]  A. Astrup,et al.  Obesity : Preventing and managing the global epidemic , 2000 .

[14]  H. Itoh,et al.  Endothelial nitric oxide synthase gene is positively associated with essential hypertension. , 1998, Hypertension.

[15]  M. Margaglione,et al.  Raised Plasma Fibrinogen Concentrations in Subjects Attending a Metabolic Ward - Relation to Family History and Vascular Risk Factors , 1995, Thrombosis and Haemostasis.

[16]  M. Hirata,et al.  Seven DNA polymorphisms at the candidate genes of atherosclerosis in Brazilian women with angiographically documented coronary artery disease. , 2000, Clinica chimica acta; international journal of clinical chemistry.

[17]  M. Hirata,et al.  Association of the Apolipoprotein B Gene Polymorphisms with Cholesterol Levels and Response to Fluvastatin in Brazilian Individuals with High Risk for Coronary Heart Disease , 2000, Clinical chemistry and laboratory medicine.

[18]  L. Iacoviello,et al.  Analysis of gene-environment interaction in coronary heart disease: fibrinogen polymorphisms as an example. , 2002, Italian heart journal : official journal of the Italian Federation of Cardiology.

[19]  A. Hamsten,et al.  Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction , 2005, Thrombosis and Haemostasis.

[20]  S. Moncada,et al.  Molecular mechanisms and therapeutic strategies related to nitric oxide , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  E. Benjamin,et al.  Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. , 2002, Journal of the American College of Cardiology.

[22]  M. Simionescu,et al.  Relationship of eNOS gene variants to diseases that have in common an endothelial cell dysfunction , 2005, Journal of cellular and molecular medicine.

[23]  C. Scavone,et al.  Expression of inducible nitric oxide synthase is increased in patients with heart failure due to ischemic disease. , 2004, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[24]  A. Hamsten,et al.  Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Gimbrone,et al.  Vascular endothelium, hemodynamic forces, and atherogenesis. , 1999, The American journal of pathology.

[26]  M Ishii,et al.  [The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, and 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension]. , 2000, Nihon rinsho. Japanese journal of clinical medicine.

[27]  C. Bode,et al.  Regulation of PAI-1 expression by genetic polymorphisms. Impact on atherogenesis. , 2001, Thrombosis research.

[28]  H Yasue,et al.  Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. , 1998, Journal of the American College of Cardiology.

[29]  V. Álvarez,et al.  Association between the NOS3 (-786 T/C) and the ACE (I/D) DNA genotypes and early coronary artery disease. , 2001, Nitric oxide : biology and chemistry.

[30]  R. Zechner,et al.  Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. , 2003, Cardiovascular research.

[31]  D. Loskutoff,et al.  Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. White,et al.  Potential thrombophilic mutations/polymorphisms in patients with no flow-limiting stenosis after myocardial infarction. , 2003, American heart journal.

[33]  S. Masetti,et al.  Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. , 2003, Clinical chemistry.

[34]  K. Nakao,et al.  T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. , 1999, Circulation.

[35]  J. Cooke Role of nitric oxide in progression and regression of atherosclerosis. , 1996, The Western journal of medicine.

[36]  P. McKeigue,et al.  Problems of reporting genetic associations with complex outcomes , 2003, The Lancet.

[37]  K. Nakao,et al.  T(-786)--> C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis. , 2000, The American journal of cardiology.

[38]  A. Hingorani,et al.  A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. , 1999, Circulation.

[39]  A. Pessina,et al.  The T-786C endothelial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study. , 2003, Journal of the American College of Cardiology.

[40]  S. Humphries,et al.  The 4G/5G Genetic Polymorphism in the Promoter of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene Is Associated with Differences in Plasma PAI-1 Activity but not with Risk of Myocardial Infarction in the ECTIM Study , 1995, Thrombosis and Haemostasis.

[41]  F. Burzotta,et al.  The 4G/5G Polymorphism of PAI-1 Promoter Gene and the Risk of Myocardial Infarction: A Meta-analysis , 1998, Thrombosis and Haemostasis.