We recently identified rs3918226 as a hypertension susceptibility locus (−665 C>T), TT homozygosity being associated with higher hypertension risk. T compared with C allele transfected cells had lower endothelial nitric oxide synthase (eNOS) expression. In the family-based Flemish Study on Environment, Genes and Health Outcomes (50.9% women; mean age 40.3 years), we investigated whether 32 TT homozygotes had worse outcomes than 2787 C allele carriers. Over 15 years (median), total and cardiovascular mortality and cardiovascular and coronary events amounted to 269 (9.5%), 98 (3.5%), 247 (8.8%) and 120 (4.3%), respectively. While accounting for family clusters, the hazard ratios associated with TT homozygosity were 4.11 (P=0.0052) for cardiovascular mortality (4 deaths), 2.75 (P=0.0067) for cardiovascular events (7 endpoints) and 3.10 (P=0.022) for coronary events (4 endpoints). With adjustment for cardiovascular risk factors, these hazard ratios were 6.01 (P=0.0003), 2.64 (P=0.0091) and 2.89 (P=0.010), respectively. Analyses unadjusted for blood pressure and antihypertensive treatment produced consistent results. For all fatal plus nonfatal cardiovascular events, the positive predictive value, attributable risk and population-attributable risk associated with TT homozygosity were 21.9, 61.5 and 2.0%, respectively. In conclusion, TT homozygosity at the position −665 in the eNOS promoter predicts adverse outcomes, independent of blood pressure and other risk factors.
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Mrs Annick De Soete and Mrs Sandra Covens provided expert clerical assistance. Sources of funding: Dr Laura Olivi was partly supported by student mobility Erasmus Placement Grant from the University of Milano. The European Union (grant FP7-HEALTH-2007-A-201550, and HYPERGENES provided financial support for the genotyping studies. The European Union InterOmics (PB05 MIUR-CNR Italian Flagship Project) supported the Department of Health Sciences-University of Milan. The European Union (grants IC15-CT98-0329-EPOGH, LSHM-CT-2006-037093-InGenious HyperCare, HEALTH-2007-2.1.1-2-HyperGenes, HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-F7-305507 HOMAGE and the European Research Council Advanced Researcher grant-2011-294713-EPLORE) gave support to the Studies Coordinating Centre, Leuven, Belgium. The Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.0880.13) also supported the FLEMENGHO study.
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Supplementary Information accompanies this paper on the Journal of Human Hypertension website (http://www.nature.com/jhh)
Frontiers in Cell and Developmental Biology (2015)