title: A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization.
abstract: Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Wendy
authors.initials: W
authors.lastname: Post
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Morna
authors.initials: M
authors.lastname: Ikeda
authors.forename: Kristen
authors.initials: K
authors.lastname: West
authors.forename: Carl
authors.initials: C
authors.lastname: Kashuk
authors.forename: Mahmut
authors.initials: M
authors.lastname: Akyol
authors.forename: Siegfried
authors.initials: S
authors.lastname: Perz
authors.forename: Shapour
authors.initials: S
authors.lastname: Jalilzadeh
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Guo
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.forename: H Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.forename: Peter M
authors.initials: PM
authors.lastname: Spooner
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D015331:Cohort Studies; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I