Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase

Abstract

Abstract-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 ). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; Pϭ1.032 ⅐ 10 Ϫ14). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16 -3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus. (Hypertension. 2012;59:248-255.) • Online Data Supplement Key Words: genetic epidemiology Ⅲ risk factors Ⅲ genetics association studies Ⅲ NO Ⅲ essential hypertension E ssential hypertension (EH) is a clinical condition affecting a large proportion (25% to 30%) of the adult population and is a major risk factor for cardiovascular and renal diseases. 1,2 It is a complex trait influenced by multiple susceptibility genes, environmental, and lifestyle factors and their interactions. 3 In the last years, huge efforts have been performed in recruiting and genotyping tens of thousands of individuals and meta-analyzing dozens of cross-sectional, population-based studies. In spite of this, the research on the genetics of EH has been frustrated by the small predictive value of the discovered genetic variants and by the fact that these variants explain a small proportion of the phenotypic variation. 4 -13 EH is a late-onset disease and, therefore, the small discovered effect sizes could in part be because of the effect of misclassification, sample selection bias, and inappropriate phenotyping of cases and controls. 9,14,15 The selection of cases and controls may have important effects on the results, because misclassification bias can lead to loss of power. For common traits, such as EH, this bias can be remedied by defining more stringent selection criteria, by recruiting hypernormal controls and adopting a more stringent case definition. 14,15 The HYPERGENES Project pursued a 2-stage study to investigate novel genetic determinants of EH. Cases and controls were recruited from extensively characterized cohorts over many years in different European regions using standardized clinical ascertainment. Particular care was devoted to c...

Reevaluation of the association of seven candidate genes with blood pressure and hypertension: a replication study and meta-analysis with a larger sample size

“…This value may not indicate the lack of modest association at these loci, as we reported in the present study (Figure 3). During the preparation of our manuscript, a multi-staged GWA study of hypertension reported a new susceptibility locus (rs3918226) in the promoter region of NOS3 in populations of European descent; 38 this SNP does not appear to be polymorphic in East Asians (according to HapMap JPT/CHB data), although further examination is warranted.…”

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…Additionally, there is evidence that the particular variant (rs3918226), which is located in the promoter of the NOS3 gene, influences the expression of eNOS with a negative effect of the risk allele (Salvi et al , 2013). As briefly discussed above, the NOS3 gene has also been associated with blood pressure (Salvi et al , 2012, 2013). Bearing in mind that NO leads to vasodilatation, this is plausible.…”

Genetic and Molecular Aspects of Hypertension

“…It is evident that the majority of BP-related GWAS SNPs are noncoding and identifying causal variants and the mechanisms through which they act present significant challenges. Although majority of GWAS studied BP as a quantitative trait, only 2 studies analyzed hypertension as a dichotomous trait, 22,29 both of which resulted in identification of tractable signals in novel or established pathways of BP regulation. 22,[29][30][31][32] One variant (rs13333226) 22 is located in the promoter region of Uromodulin gene (UMOD), which is exclusively expressed in the kidney and possibly affects BP through a novel sodium homeostatic pathway, whereas second promoter SNP lies near the endothelial nitric oxide synthase (eNOS) gene, which is known to mediate vascular tone.…”