title: The -665 C>T polymorphism in the eNOS gene predicts cardiovascular mortality and morbidity in white Europeans.
abstract: 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.
authors.affiliation: 1] Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium [2] Department of Health Sciences and Graduate School of Nephrology, University of Milan, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Olivi
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Y M
authors.initials: YM
authors.lastname: Gu
authors.affiliation: Department of Health Sciences and Graduate School of Nephrology, University of Milan, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Salvi
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
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authors.initials: YP
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authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: L
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authors.lastname: Thijs
authors.affiliation: 1] Department of Health Sciences and Graduate School of Nephrology, University of Milan, Milan, Italy [2] Genomic and Bioinformatics Units, Filarete Foundation, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Velayutham
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: 1] Department of Health Sciences and Graduate School of Nephrology, University of Milan, Milan, Italy [2] Genomic and Bioinformatics Units, Filarete Foundation, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: D'Avila
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Petit
authors.affiliation: 1] Department of Health Sciences and Graduate School of Nephrology, University of Milan, Milan, Italy [2] Genomic and Bioinformatics Units, Filarete Foundation, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Barcella
authors.affiliation: Department of Nephrology and Dialysis, Universitá Vita Salute San Raffaele, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Lanzani
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Kuznetsova
authors.affiliation: Department of Nephrology and Dialysis, Universitá Vita Salute San Raffaele, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Manunta
authors.affiliation: 1] Department of Health Sciences and Graduate School of Nephrology, University of Milan, Milan, Italy [2] Genomic and Bioinformatics Units, Filarete Foundation, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Barlassina
authors.affiliation: 1] Department of Health Sciences and Graduate School of Nephrology, University of Milan, Milan, Italy [2] Genomic and Bioinformatics Units, Filarete Foundation, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cusi
authors.affiliation: 1] Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium [2] Department of Epidemiology, Maastricht University, Maastricht, Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Staessen
mesh_terms: D000328:Adult; D001530:Belgium / Q000453:epidemiology; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
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