Endothelial Nitric Oxide Synthase Haplotypes Research Articles

Endothelial Nitric Oxide Synthase Haplotypes Associated with Aura in Patients with Migraine

There is strong evidence implicating nitric oxide (NO) in the pathophysiology of migraine and aura. Therefore, genetic polymorphisms in the endothelial NO synthase (eNOS) gene have been studied as candidate markers for migraine susceptibility. We compared for the first time the distribution of eNOS haplotypes including the three clinically relevant eNOS polymorphisms (T(-786)C in the promoter, rs2070744; Glu298Asp in exon 7, rs1799983; and a 27 bp variable number of tandem repeats in intron 4) and two additional tagging single-nucleotide polymorphisms (rs3918226 and rs743506) in 178 women with migraine (134 without aura and 44 with aura) and 117 healthy controls (control group). Genotypes were determined by TaqMan allele discrimination assay, real-time polymerase chain reaction, and polymerase chain reaction followed by fragment separation by electrophoresis. The GA (rs743506) genotype was more common in the control group than in women with migraine (odds ratio = 0.47, 95% confidence interval [CI] = 0.29-0.78, p < 0.01). No significant differences were found in allele distributions for the five eNOS polymorphisms. However, the haplotypes including the variants "C C a Glu G" and the variants "C C b Glu G" were more common in women with migraine with aura than in women with migraine without aura (odds ratio = 30.71, 95% CI = 1.61-586.4 and odds ratio = 17.26, 95% CI = 1.94-153.4, respectively; both p < 0.0015625). These findings suggest that these two eNOS haplotypes affect the susceptibility to the presence of aura in patients with migraine.

Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Preeclampsia in Maya Mestizo Women

Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms ineNOSor their haplotypes are associated with preeclampsia in Maya mestizo women.A case-control study was performed where 127 preeclamptic patients and 263 controls were included. Genotyped and haplotypes for the -768T→C, intron 4 variants, Glu298Asp ofeNOSwere determined by PCR and real-time PCR allelic discrimination. Logistic regression analysis with adjustment for age and body mass index (BMI) was used to test for associations between genotype and preeclampsia under recessive, codominant and dominant models. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlationr2, and haplotype analysis was conducted.Women homozygous for the Asp298 allele showed an association of preeclampsia. In addition, analysis of the haplotype frequencies revealed that the -786C-4b-Asp298 haplotype was significantly more frequent in preeclamptic patients than in controls (0.143 vs. 0.041, respectively; OR = 3.01; 95% CI = 1.74–5.23;P= 2.9 × 10−4).Despite the Asp298 genotype in a recessive model associated with the presence of preeclampsia in Maya mestizo women, we believe that in this population the -786C-4b-Asp298 haplotype is a better genetic marker.

Endothelial nitric oxide synthase haplotypes are associated with preeclampsia in Maya mestizo women.

Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms in eNOS or their haplotypes are associated with preeclampsia in Maya mestizo women.A case-control study was performed where 127 preeclamptic patients and 263 controls were included. Genotyped and haplotypes for the -768T→C, intron 4 variants, Glu298Asp of eNOS were determined by PCR and real-time PCR allelic discrimination. Logistic regression analysis with adjustment for age and body mass index (BMI) was used to test for associations between genotype and preeclampsia under recessive, codominant and dominant models. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis was conducted.Women homozygous for the Asp298 allele showed an association of preeclampsia. In addition, analysis of the haplotype frequencies revealed that the -786C-4b-Asp298 haplotype was significantly more frequent in preeclamptic patients than in controls (0.143 vs. 0.041, respectively; OR = 3.01; 95% CI = 1.74–5.23; P = 2.9 × 10−4).Despite the Asp298 genotype in a recessive model associated with the presence of preeclampsia in Maya mestizo women, we believe that in this population the -786C-4b-Asp298 haplotype is a better genetic marker.

Endothelial Nitric Oxide Synthase Haplotypes Associated with Hypertension Do Not Predispose to Cardiac Hypertrophy

Left ventricular hypertrophy (LVH) is a complication that may result from chronic hypertension. While nitric oxide (NO) deficiency has been associated with LVH, inconsistent results have been reported with regards to the association of endothelial NO synthase (eNOS) polymorphisms and LVH in hypertensive patients. This study aims to assess whether eNOS haplotypes are associated with LVH in hypertensive patients. This study included 101 healthy controls and 173 hypertensive patients submitted to echocardiography examination. Genotypes for three eNOS polymorphisms were determined: a single-nucleotide polymorphism in the promoter region (T-786C) and in exon 7 (Glu298Asp), and variable number of tandem repeats in intron 4. We found no significant association between eNOS genotypes and hypertension or with LVH (all p > 0.05). However, while we found two eNOS haplotypes associated with variable risk of hypertension (all p < 0.05), we found no significant associations between eNOS haplotypes and LVH (all p > 0.05), even after adjustment in multiple linear regression analysis. These findings suggest that eNOS haplotypes that have been associated with variable susceptibility to hypertension were not associated with LVH in hypertensive patients. Further studies are necessary to examine whether other genes downstream may interact with eNOS polymorphisms and predispose to LVH in hypertensive patients.

Endothelial nitric oxide synthase polymorphisms and hypertension: Improved clinical evidence derived from haplotype analysis

Khawaja et al. have recently reported a clinical study addressing the possible association between the G894T polymorphism in the exon 7 of endothelial nitric oxide (eNOS) gene and hypertension in adult Pakistani Patan [ [1] Khawaja M.R. Taj F. Ahmad U. Saleheen D. Jafar T. Frossard P.M. Association of endothelial nitric oxide synthase gene G894T polymorphism with essential hypertension in an adult Pakistani Pathan population. Int J Cardiol. 2006; 116: 107-112 PubMed Google Scholar ]. They found lack of significant association between this eNOS polymorphism and hypertension in that specific population. However, it has been widely acknowledged that haplotype (combination of genetic markers within a specific chromosome cluster location) analysis can provide much more useful information in association studies than the information derived from single polymorphisms analysis [ 2 Crawford D.C. Nickerson D.A. Definition and clinical importance of haplotypes. Annu Rev Med. 2005; 56: 303-320 Crossref PubMed Scopus (260) Google Scholar , 3 Johnson G.C. Esposito L. Barratt B.J. et al. Haplotype tagging for the identification of common disease genes. Nat Genet. 2001; 29: 233-237 Crossref PubMed Scopus (1021) Google Scholar ]. Indeed, we have recently reported that eNOS haplotypes involving three polymorphisms are associated with the development of hypertension [ 4 Sandrim V.C. de Syllos R.W.C. Lisboa H.R.K. Tres G.S. Tanus-Santos J.E. Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus. Atherosclerosis. 2006; 189: 241-246 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar , 5 Sandrim V.C. Coelho E.B. Nobre F. Arado G.M. Lanchote V.L. Tanus-Santos J.E. Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis. 2006; 186: 428-432 Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar , 6 Sandrim V.C. Yugar-Toledo J.C. Desta Z. Flockhart D.A. Moreno Jr., H. Tanus-Santos J.E. Endothelial nitric oxide synthase haplotypes and resistance to antihypertensive drug therapy. J Hypertens. 2006; 24: 2393-2397 Crossref PubMed Scopus (53) Google Scholar ]. Our findings would have been obscured if specific eNOS genotypes alone had been considered [ 4 Sandrim V.C. de Syllos R.W.C. Lisboa H.R.K. Tres G.S. Tanus-Santos J.E. Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus. Atherosclerosis. 2006; 189: 241-246 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar , 5 Sandrim V.C. Coelho E.B. Nobre F. Arado G.M. Lanchote V.L. Tanus-Santos J.E. Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis. 2006; 186: 428-432 Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar , 6 Sandrim V.C. Yugar-Toledo J.C. Desta Z. Flockhart D.A. Moreno Jr., H. Tanus-Santos J.E. Endothelial nitric oxide synthase haplotypes and resistance to antihypertensive drug therapy. J Hypertens. 2006; 24: 2393-2397 Crossref PubMed Scopus (53) Google Scholar ]. Of note, we found that specific eNOS haplotypes, but not genotypes, are associated with susceptibility to hypertension [ 4 Sandrim V.C. de Syllos R.W.C. Lisboa H.R.K. Tres G.S. Tanus-Santos J.E. Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus. Atherosclerosis. 2006; 189: 241-246 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar , 5 Sandrim V.C. Coelho E.B. Nobre F. Arado G.M. Lanchote V.L. Tanus-Santos J.E. Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis. 2006; 186: 428-432 Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar , 6 Sandrim V.C. Yugar-Toledo J.C. Desta Z. Flockhart D.A. Moreno Jr., H. Tanus-Santos J.E. Endothelial nitric oxide synthase haplotypes and resistance to antihypertensive drug therapy. J Hypertens. 2006; 24: 2393-2397 Crossref PubMed Scopus (53) Google Scholar ]. Importantly, we found that the same specific eNOS haplotypes are associated with susceptibility to hypertension in subjects with different ethnic backgrounds [ [5] Sandrim V.C. Coelho E.B. Nobre F. Arado G.M. Lanchote V.L. Tanus-Santos J.E. Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis. 2006; 186: 428-432 Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar ], even though huge interethnic differences exist in the distribution of eNOS genotypes or haplotypes [ 7 Tanus-Santos J.E. Desai M. Flockhart D.A. Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics. 2001; 11: 719-725 Crossref PubMed Scopus (258) Google Scholar , 8 Marroni A.S. Metzger I.F. Souza-Costa D.C. et al. Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase genetic polymorphisms. Nitric Oxide. 2005; 12: 177-182 Crossref PubMed Scopus (138) Google Scholar ]. Our data support the idea that the interaction of multiple eNOS polymorphism plays a role in the susceptibility to hypertension. This susceptibility associated with eNOS gene would hardly be found in single polymorphism studies.

Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Features of Metabolic Syndrome

The metabolic syndrome, a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Endothelium-derived nitric oxide facilitates skeletal muscle glucose uptake, and data from animal models indicate that endothelial nitric oxide synthase (eNOS) gene-null mice present with a phenotype of insulin resistance, hypertension, and hypertriglyceridemia, much like that observed in humans with metabolic syndrome. We used haplotype tagging single nucleotide polymorphisms (htSNPs) to investigate the role of genetic variation in the eNOS gene (NOS3) in metabolic syndrome in humans. We recruited 738 unrelated persons from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Metabolic syndrome was defined according to the recently modified National Cholesterol Education Program Adult Treatment Panel III guidelines. Haplotype analysis showed a statistically significant association between some NOS3 gene variants and features of metabolic syndrome. Relative to the most common haplotype, 121, the haplotype 212 was associated with an increased odds ratio (OR) for metabolic syndrome [OR = 1.81, 95% confidence interval (CI) 1.15-2.84], and for decreased HDL-cholesterol concentrations (OR 1.52, 95% CI 1.01-2.29), and with increased mean values for the homeostasis model assessment of insulin resistance (P = 0.043), and triglycerides (P = 0.026). Our results suggest that genetic variation at the eNOS locus is associated with features of metabolic syndrome, and might represent a new genetic susceptibility component for insulin resistance, hypertriglyceridemia, and low HDL-cholesterol concentrations.

Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy

Most hypertensive patients require two or more drugs to control arterial blood pressure effectively. Although endothelial nitric oxide synthase (eNOS) haplotypes have been associated with hypertension, it is unknown whether eNOS genotypes/haplotypes are associated with resistance to antihypertensive therapy. We studied the distribution of three eNOS genetic polymorphisms: single nucleotide polymorphisms in the promoter region (T(-786)C), and in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a). Genotypes were determined for 111 normotensive controls (NT), 116 hypertensive individuals who were well controlled (HT), and 100 hypertensive individuals who were resistant to conventional antihypertensive therapy (RHT). We also compared the distribution of eNOS haplotypes in the three groups of subjects. No differences were found in genotype or allele distribution among the three groups (all P > 0.05). Conversely, the 'C Glu b' haplotype was more commonly found in the NT than in the HT or RHT groups (21 versus 8 and 7%, respectively; both P < 0.00625). In addition, the 'C Asp b' haplotype was more commonly found in the HT or RHT groups than in the NT group (22 and 20%, respectively, versus 8%; both P < 0.00625). The distribution of eNOS haplotypes was not significantly different in the HT and RHT groups (P > 0.05). Whereas our findings suggest a protective effect for the 'C Glu b' haplotype against hypertension and that the 'C Asp b' haplotype increases the susceptibility to hypertension, our results suggest that eNOS haplotypes are not associated with resistance to antihypertensive therapy.

Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) and hypertension (HT) commonly coexist. While endothelial nitric oxide synthase (eNOS) haplotypes have been associated with HT, it is unknown whether eNOS genotypes/haplotypes are associated with altered susceptibility to HT in patients with T2DM. We studied the distribution of three eNOS genetic polymorphisms: a single nucleotide polymorphism in the promoter region (T −786C), in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a). Genotypes were determined for 102 healthy controls, 119 patients with HT, 66 patients with T2DM, and 113 patients with T2DM + HT. In addition, we also compared the distribution of eNOS haplotypes in the four groups of subjects. No differences were found in genotype and allele distribution among the four groups. Conversely, the haplotypes “C Glu b” and “C Asp b” were, respectively, more and less common in healthy controls than in HT or in T2DM + HT groups (24% versus 6% and 5%, respectively; both P < 0.00625; and 8% versus 18% and 18%, respectively; both P < 0.00625). Moreover, DM patients presented an overall distribution of eNOS haplotypes that was not different from healthy controls ( P > 0.05). Additionally, the haplotypes “C Glu b” and “C Asp b” were, respectively, more and less common in T2DM group than in T2DM + HT group (19% versus 5%; and 7% versus 18%, respectively; both P < 0.00625). Our findings suggest a protective effect for eNOS haplotype “C Glu b” against the development of hypertension, and that haplotype “C Asp b” increases the susceptibility to hypertension in patients without or with T2DM.

S.03.04 Neuronal and endothelial nitric oxide synthase haplotypes are associated with endogenous psychoses

S.03.04 Neuronal and endothelial nitric oxide synthase haplotypes are associated with endogenous psychoses