Ortu, Maria Francesca (2013) Genome-wide 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. Doctoral Thesis.
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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.
Aim: 1. To identify the genes responsible for Essential hypertension (EH) through entropy-based Whole Genome Association.
2. To develop an integrated model of disease considering the environment, using an advanced bioinformatics approach.
3. To validate the ability of the conceptual model we adopted to identify individuals at risk.
Methods: In the Discovery phase the samples were genotyped using the Illumina 1M-duoArray. To validate and fine map the genes found associated with EH in discovery phase an Illumina custom chip of 14,055 markers was created starting from the list of best-associated and of candidate SNPs.
Results: We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial nitric oxide synthase (eNOS) gene (odds ratio 1.54; 95% CI 1.37-1.73; combined p=2.58∙10 -13). The finding was also meta-analyzed using other in-silico/de novo genotyping data resulting in an overall OR of 1.34 (95% CI 1.25-1.44, p=1.032∙10-14).
Conclusion: With a stringent case-control design and a population based study, we identified a novel hypertension susceptibility locus in the promoter region of eNOS with a relatively high effect size. Our finding could provide new insights into the mechanism of vascular regulation and could help in better understanding the genetics of EH.
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