Endothelial NO Synthase Gene Polymorphisms and Hypertension: A Meta-Analysis

Studies investigated the association between endothelial NO synthase gene polymorphisms and hypertension-reported contradicted or nonconclusive results. A meta-analysis of 35 genetic association studies that examined the relation between hypertension and the G894T, 4a/b, T786C, and G23T polymorphisms of the endothelial nitric oxide synthase gene was carried out. Subgroup analysis by ethnicity and potential sources of heterogeneity and bias were explored. The meta-analysis included genotype data on 7779/10 498, 2216/3222, 2491/3913, and 833/587 cases/controls for G894T, 4b/a, T786C, and G23T, respectively. For the 4b/a polymorphism, overall, the heterogeneity between studies was not significant (P =0.82), and the allele b was associated with a 15% decreased risk of hypertension relative to allele a (odds ratio: 0.85; 95% CI: 0.74 to 0.98). Overall and in whites, the recessive model for allele b produced significant results (odds ratios: 0.78; 95% CI: 0.68 to 0.90 and OR: 0.76 95% CI: 0.62 to 0.92, respectively), whereas the dominant model produced nonsignificant results. In studies involved East Asians and blacks, an association was not demonstrated. Regarding the G894T, T768C, and G23T polymorphisms, in no case (ie, overall, in whites, or in East Asians) was a statistically significant association and heterogeneity found. There was no substantial source of bias in the selected studies. In conclusion, there is evidence of association only between 4b/a polymorphism and hypertension; however, studies exploring combinations of the polymorphisms may help us better understand the genetics of hypertension.

[1]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[2]  D. Müller-Wieland,et al.  Peroxisome proliferator-activated receptor-gamma2 Pro12Ala and endothelial nitric oxide synthase-4a/b gene polymorphisms are not associated with hypertension in diabetes mellitus type 2. , 2005, Journal of hypertension.

[3]  N. Derebecka,et al.  Polymorphism in intron 23 of the endothelial nitric oxide synthase gene (NOS3) is not associated with hypertension. , 2002, Acta biochimica Polonica.

[4]  J. Tanus-Santos,et al.  Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. , 2006, Atherosclerosis.

[5]  I. Stefanidis,et al.  The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis , 2005, Journal of Human Genetics.

[6]  R. Ramírez-Lorca,et al.  Association of NOS3 gene with metabolic syndrome in hypertensive patients , 2004, Thrombosis and Haemostasis.

[7]  Thomas A Trikalinos,et al.  Genetic associations in large versus small studies: an empirical assessment , 2003, The Lancet.

[8]  D. Alavantic,et al.  Endothelial NOS G894 T and MMP‐3 5A/6A gene polymorphisms and hypertension in Serbian population , 2005, Journal of clinical laboratory analysis.

[9]  Y. Kawaguchi,et al.  An Intron 4 Gene Polymorphism in Endothelial Cell Nitric Oxide Synthase Might Modulate Volume-Dependent Hypertension in Patients on Hemodialysis , 2000, Nephron.

[10]  T. Nakayama,et al.  Association of a variable number of tandem repeats in the endothelial constitutive nitric oxide synthase gene with essential hypertension in Japanese. , 1998, American journal of hypertension.

[11]  X. Jeunemaître,et al.  Lack of evidence for linkage of the endothelial cell nitric oxide synthase gene to essential hypertension. , 1995, Circulation.

[12]  M. Ikäheimo,et al.  Endothelial nitric oxide synthase gene Glu298Asp polymorphism and blood pressure, left ventricular mass and carotid artery atherosclerosis in a population‐based cohort , 2002, Journal of internal medicine.

[13]  E. Boerwinkle,et al.  Combined effects of endothelial nitric oxide synthase gene polymorphism (G894T) and insulin resistance status on blood pressure and familial risk of hypertension in young adults: the Bogalusa Heart Study. , 2001, American journal of hypertension.

[14]  M. Moskowitz,et al.  Hypertension in mice lacking the gene for endothelial nitric oxide synthase , 1995, Nature.

[15]  U. John,et al.  Endothelial nitric oxide synthase Glu298Asp gene polymorphism, blood pressure and hypertension in a general population sample , 2005, Journal of hypertension.

[16]  John P A Ioannidis,et al.  Heterogeneity testing in meta‐analysis of genome searches , 2005, Genetic epidemiology.

[17]  S. Thompson,et al.  Quantifying heterogeneity in a meta‐analysis , 2002, Statistics in medicine.

[18]  Elias Zintzaras,et al.  Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis , 2005, Journal of Human Genetics.

[19]  M. Yasujima,et al.  Positive association of endothelial nitric oxide synthase gene polymorphism with hypertension in northern Japan. , 2000, Life sciences.

[20]  Tomomi Kimura,et al.  NOS3 Genotype–Dependent Correlation Between Blood Pressure and Physical Activity , 2003, Hypertension.

[21]  Ihab Hajjar,et al.  Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. , 2003, JAMA.

[22]  E. Zintzaras,et al.  Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta‐analysis , 2006, Clinical genetics.

[23]  T C Chalmers,et al.  Cumulative meta-analysis of therapeutic trials for myocardial infarction. , 1992, The New England journal of medicine.

[24]  S. Giannouli,et al.  A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia , 2006, European Journal of Epidemiology.

[25]  David Clayton,et al.  Epidemiological methods for studying genes and environmental factors in complex diseases , 2001, The Lancet.

[26]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[27]  Y. Yazaki,et al.  Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension. , 1999, Hypertension.

[28]  K. Kawecka-Jaszcz,et al.  Ambulatory blood pressure, left ventricular mass and vascular phenotypes in relation to the endothelial nitric oxide synthase gene Glu298Asp and intron 4 polymorphisms in a population-based family study , 2005, Journal of Human Hypertension.

[29]  J. Ioannidis,et al.  Evolution of treatment effects over time: empirical insight from recursive cumulative metaanalyses. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  G. Chase,et al.  Genome scan meta-analysis for hypertension. , 2004, American journal of hypertension.

[31]  Jeffrey Ross-Ibarra,et al.  Genetic Data Analysis II. Methods for Discrete Population Genentic Data , 2002 .

[32]  L. Ignarro,et al.  Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[33]  T. Ogihara,et al.  Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: The Suita Study , 2001, Journal of hypertension.

[34]  F. Cambien,et al.  Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects , 1998, Journal of hypertension.

[35]  S. Humphries,et al.  Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease: Meta-Analysis of 26 Studies Involving 23028 Subjects , 2004, Circulation.

[36]  G. D. Thomas,et al.  Nitric oxide deficiency as a cause of clinical hypertension: promising new drug targets for refractory hypertension. , 2001, JAMA.

[37]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.

[38]  L. Ghiadoni,et al.  The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. , 2003, Journal of the American College of Cardiology.

[39]  M. Savolainen,et al.  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 , 2001, Journal of internal medicine.

[40]  K. Nakao,et al.  Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T-786-->C and missense Glu298Asp variants. , 2000, Journal of investigative medicine : the official publication of the American Federation for Clinical Research.

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

[42]  M. Munafo,et al.  Meta-analysis of genetic association studies. , 2004, Trends in genetics : TIG.

[43]  Elias Zintzaras,et al.  Association of paraoxonase 1 gene polymorphisms with risk of Parkinson′s disease: a meta-analysis , 2004, Journal of Human Genetics.

[44]  D. Dudley,et al.  Haplotype-Specific Effects on Endothelial NO Synthase Promoter Efficiency: Modifiable by Cigarette Smoking , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[45]  John P. A. Ioannidis,et al.  HEGESMA: genome search meta-analysis and heterogeneity testing , 2005, Bioinform..

[46]  J. Rodriguez-Perez,et al.  Peroxisome proliferator-activated receptor-gamma2-Pro12Ala and endothelial nitric oxide synthase-4a/b gene polymorphisms are associated with essential hypertension , 2003, Journal of hypertension.

[47]  M. Inaba,et al.  Relations between ACE gene and ecNOS gene polymorphisms and resistive index in type 2 diabetic patients with nephropathy. , 2001, Diabetes care.

[48]  Y. Osaki,et al.  eNOS Glu298Asp polymorphism and hypertension in a cohort study in Japanese. , 2004, Preventive medicine.

[49]  M. Margaglione,et al.  Does Endothelial Nitric Oxide Synthase Gene Variation Play a Role in the Occurrence of Hypertension in Pregnancy? , 2003, Hypertension in pregnancy.

[50]  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.

[51]  K. Nakao,et al.  Lack of association between T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene and essential hypertension. , 2000, Hypertension research : official journal of the Japanese Society of Hypertension.

[52]  S. Hazzaa,et al.  Nitric oxide synthase gene G298 allele. Is it a marker for microvascular angina in hypertensive patients? , 2004, Cardiovascular radiation medicine.

[53]  S. Humphries,et al.  Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease Meta-Analysis of 26 Studies Involving 23 028 Subjects , 2004 .

[54]  J. Krieger,et al.  Endothelial nitric oxide synthase gene variant modulates the relationship between serum cholesterol levels and blood pressure in the general population: new evidence for a direct effect of lipids in arterial blood pressure. , 2006, Atherosclerosis.

[55]  E. Lonn,et al.  The T-786→C Mutation in Endothelial Nitric Oxide Synthase Is Associated With Hypertension , 2002, Hypertension.

[56]  B. Morris,et al.  Association analyses of endothelial nitric oxide synthase gene polymorphisms in essential hypertension. , 2000, American journal of hypertension.

[57]  Thomas A Trikalinos,et al.  'Racial' differences in genetic effects for complex diseases , 2004, Nature Genetics.

[58]  J. Peleska,et al.  Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy. , 2001, Biochemical and biophysical research communications.