Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias (original) (raw)
Hypertension, 2012
Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping d...
Biointerface Research in Applied Chemistry
The vascular endothelium is one of the earliest damage-targeted hypertensive-mediated organs. The study aims to analyze the link of metabolic disorders with endothelial dysfunction (ED) and NOS3 (rs2070744) and GNB3 (rs5443) genes polymorphism in essential arterial hypertension (EAH). One hundred EAH patients (48 – healthy control) participated in the case-control study. Creatinine, glucose, triglycerides, total cholesterol (TC), low/high-density lipoproteins values (LDL-C, HDL-C), Atherogenicity Index (AI), Soluble Vascular Cell Adhesion Molecule, total NO metabolites (NO2-/NO3-) were studied. GNB3 (rs5443) and NOS3 (rs2070744) genotyping performed by TaqMan probes (CFX96™Real-Time PCR). Moderate-severe ED in EAH patients associated with higher blood pressure – by 6.90% and 4.69% (Р<0.05), creatinine blood increase – by 10.08% (Р=0.037), profound dysmetabolic changes but only in men: hyperglycemia by 46.46% (Р=0.004), hypercholesterolemia and lower HDL-C content by 15.79% (Р=0.0...
Journal of Human Hypertension, 2006
Vascular endothelial cells produce nitric oxide (NO), which contributes to the regulation of blood pressure and regional blood flow. Endothelial nitric oxide synthase (eNOS) gene polymorphisms are associated with coronary artery disease, but their linkage with primary hypertension is controversial. A total of 103 individuals with primary hypertension and 104 normotensive control subjects were studied in Singapore. The specific genotypes for G894T missense variant in exon 7, variable number tandem repeats (VNTR) in intron 4 (eNOS 4A/B/C) and TÀ786C in the promoter were isolated using allele-specific gene amplification and restriction fragment length polymorphism to examine the association of genotype and allelic frequency in both groups. Logistic regression analysis was also used to detect the association between genotypes and hypertension. Five genotypes of intron 4 VNTR (AA, AB, BB, AC and BC) were observed. Intron 4 B/B genotype was significantly associated with the hypertension group (P ¼ 0.035), but disequilibrium of G894T and TÀ786C was absent between the two groups (P ¼ 0.419 and P ¼ 0.227), respectively. The overall distribution of allelic frequency differed significantly between the two groups, with four-repeat allele (4A) of intron 4 more frequent in the normotensive group than the hypertensive group (P ¼ 0.019). Logistic regression analysis showed that intron 4 B/B genotype was significantly associated with systolic blood pressure of individuals with body mass index greater than 25 kg/m 2 (P ¼ 0.04).
Hypertension Research, 2012
To obtain evidence for blood pressure (BP) trait association, we conducted an association study of selected candidate gene variants. In Japan, a total of 19 426 individuals underwent testing for genetic associations with systolic BP (SBP)/diastolic BP (DBP) and 9271 individuals (3460 cases and 5811 controls) underwent testing for genetic associations with dichotomous hypertension. Association with seven notable candidate genes was tested, namely, ACE, ADD1, ADRB2, AGT, CYP11B2, GNB3 and NOS3, followed by a joint meta-analysis involving previously reported multi-study populations, including 420 000 individuals (for SBP/DBP) and 417 000 individuals (for hypertension). BP trait associations at two loci (AGT rs699 and CYP11B2 rs1799998) were consistently replicated in the Japanese association study and joint meta-analysis involving the populations described above. Hypertension association reached genome-wide significance for the two variants, specifically, P ¼ 7.3 Â 10 À10 for AGT rs699 and P ¼ 3.9 Â 10 À8 for CYP11B2 rs1799998. In our study panels, the most significant association was found for CYP11B2 rs1799998 with all three BP traits: P ¼ 1.5 Â 10 À5 for SBP, P ¼ 1.8 Â 10 À5 for DBP and P ¼ 2.3 Â 10 À5 for hypertension. A suggestive association with SBP (P ¼ 0.042), DBP (P ¼ 0.01) and hypertension (P ¼ 1.4 Â 10 À5 ) was also detected for ACE rs4340 (a proxy for ACE D/I polymorphism) in the joint meta-analysis. Our data provide evidence for true BP trait associations with two candidate gene variants. These variants were not identified in the previous genome-wide association studies, presumably because they did not reach a given threshold in the discovery stage. Thus, certain variants in genes with clinical and physiological relevance are likely to account for a portion of BP variance in the general population and are worth following up via a target gene approach.
Atherosclerosis, 2006
We investigated the association of endothelial nitric oxide synthase ( NOS3 ) polymorphisms rs2070744 ( -786T Ͼ C), 27-bp repeat 4b/4a, rs1799983 (Glu298Asp), rs3918188 ( -734C Ͼ A), and rs743507 (113G Ͼ A) with idiopathic recurrent miscarriage (IRM). This was a case-control study involving women with confi rmed IRM (n ϭ 296), and 305 age-and ethnically matched control women. NOS3 rs2070744, rs1799983, rs3918188, and rs743507 genotyping was done by TaqMan assays; NOS3 4b/4a genotyping was done by PCR-ASA. A higher frequency of -786C and 298Asp alleles was seen in IRM cases, which remained associated independently with IRM on multivariate analysis. Allele and genotype distribution of 4b/4a, rs3918188 ( -734C Ͼ A) and rs743507 (113A Ͼ G) were comparable between IRM cases and control women. Taking homozygous wild-type genotype as a reference, regression analysis confi rmed the association of Glu298Asp and -786T/C, and rs743507 homozygous carriers with IRM risk. Marked linkage disequilibrium was seen between tested NOS3 variants, thus allowing the construction of 5-locus [ -786T Ͼ C/4b4a/Glu298Asp/-734C Ͼ A/113G Ͼ A] haplotypes. Taking the common T4 b GCA haplotype as a reference, multivariate analysis confi rmed the positive association of C4 b TCG haplotype with IRM, after controlling for traditional covariates. Genetic variation at the NOS3 locus represents a genetic risk factor for increased susceptibility to IRM.
Endothelial NO Synthase Gene Polymorphisms and Hypertension
2010
was not significant (P0.82), 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
Nitric Oxide, 2015
Objective: Nitric oxide plays an important role in vascular biology. Several single nucleotide polymorphisms (SNP) in the endothelial nitric oxide gene (NOS3) have been previously associated with arterial hypertension. We investigated whether these SNPs might be associated with arterial phenotypes in the Czech general population. Methods: We genotyped three NOS3 SNPs in 426 subjects not treated for arterial hypertension (mean age, 49.1 years; 55.9% women). Arterial properties were measured using applanation tonometry. In multivariate-adjusted analyses, we assessed the gene effects of rs3918226 (−665 C > T), rs1799983 (glu298asp G > T) and rs2070744 (786 T > C) on augmentation index (AIx), central augmentation pressure (AP) and aortic pulse wave velocity (PWV). Results: Carriers of rs3918226 mutated T allele had marginally higher AIx (145.3 ± 2.5 vs. 140.2 ± 1.1%; P = 0.064) and significantly higher AP (12.7 ± 0.7 vs. 11.1 ± 0.3 mm Hg; P = 0.033). These associations were independent of potential confounding factors. Aortic PWV was not different in the two rs39182226 genotypes groups (P = 0.35). In single gene analyses, we did not observe any association between measured phenotypes and rs1799983 or rs2070744 (P ≥ 0.11). In haplotype analysis, we observed trend for higher PWV in haplotypes containing rs3918226 mutated T allele compared with other allelic combination (P ≤ 0.079). Conclusion: Mutated T allele of rs3918226 polymorphism in NOS3 gene was associated with parameters reflecting central arterial stiffness and wave reflection. We hypothesize that genetic modulation of intermediate arterial phenotypes might lead to higher blood pressure.
Free Radical Biology and Medicine, 2008
Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been associated with variations in nitric oxide (NO) formation and response to drugs in white subjects. We examined whether genetic polymorphisms (T-786C, b/a intron 4 and Glu298Asp) and haplotypes of the eNOS gene affect NO formation in 179 healthy black subjects. To assess NO formation, we measured the concentrations of nitrite in the plasma, red blood cells and whole blood. Although we found no effects of individual eNOS polymorphisms on NO formation, we found that the 'C-4b-Glu' haplotype is significantly more common in subjects with low circulating plasma and whole blood nitrite concentrations compared with subjects with high circulating nitrite concentrations (both Po0.0007). These findings reproduce previous findings in white subjects and are consistent with the idea that defining genetic markers is more important than ethnic classification, at least in terms of NO formation.