title: Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias.
abstract: BACKGROUND
  Studies on the relationship between endothelial nitric oxide (NOS3) gene variants and hypertension have been conflicting. To explore this hypothesis further, we performed a meta-analysis and re-evaluated the relationship between the three most widely studied NOS3 polymorphisms and hypertension status and blood pressure levels.
  
  
  METHODS
  Data on 40,413 subjects from 53 studies were combined in five distinct meta-analyses, and heterogeneity and publication bias were explored.
  
  
  RESULTS
  Heterogeneity was observed in all meta-analyses. By a random-effects model, carriers of the four 27-basepair repeat variable number of tandem repeats in intron 4 were associated with a 28% increase in the risk of hypertension compared with those homozygous for the 5 repeat: odds ratio (OR) 1.28, 95% confidence interval (CI) 1.11-1.47, P=0.001. In Asian individuals, Asp allele carriers displayed a similar association: OR 1.28, 95% CI 1.06-1.54, P=0.01, as well as a 2 mmHg increase in both systolic (P=0.04) and diastolic (P=0.009) blood pressure levels. Furthermore, meta-regression analysis indicated that the effect of the Glu298Asp genotype on the risk of hypertension might be dependent on total cholesterol status. No effect of the T-786C variant on hypertension was detected. There was evidence that such findings might be a result of selectively reporting/publishing positive reports.
  
  
  CONCLUSIONS
  Our results suggest that current data on the relationship between NOS3 variants and hypertension are subject not only to important heterogeneity but also to publication bias. Future research should preferentially focus on gene-environment interactions as well as haplotype analyses.
authors.affiliation: Heart Institute (InCor), São Paulo University Medical School, University of São Paulo, Brazil.
authors.forename: Tiago V
authors.initials: TV
authors.lastname: Pereira
authors.forename: Martina
authors.initials: M
authors.lastname: Rudnicki
authors.forename: Bernard M Y
authors.initials: BM
authors.lastname: Cheung
authors.forename: Larry
authors.initials: L
authors.lastname: Baum
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Paulo S L
authors.initials: PS
authors.lastname: Oliveira
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Pereira
authors.forename: José E
authors.initials: JE
authors.lastname: Krieger
mesh_terms: D000483:Alleles; D001794:Blood Pressure; D018740:Genetic Heterogeneity; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017594:Publication Bias; D012307:Risk Factors
chemical_list: D052250:Nitric Oxide Synthase Type III