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

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.