The-665 C>T polymorphism in the eNOS gene predicts cardiovascular mortality and morbidity in white Europeans

L. Olivi, Y. M. Gu, E. Salvi, Y. P. Liu, L. Thijs, D. Velayutham, Y. Jin, L. Jacobs, F. D'Avila, T. Petit, M. Barcella, C. Lanzani, T. Kuznetsova, P. Manunta, C. Barlassina, D. Cusi, J. A. Staessen

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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.

Original languageEnglish
Pages (from-to)167-172
Number of pages6
JournalJournal of Human Hypertension
Issue number3
Publication statusPublished - Jan 1 2015

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)


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