title: Polymorphisms of genes of the cardiac calcineurin pathway and cardiac hypertrophy.
abstract: The study investigated the role of genetic polymorphisms in four genes of the calcineurin pathway on cardiac hypertrophy and dilated cardiomyopathy. The cardiac calcineurin pathway has been suggested to play a role in the development of cardiac hypertrophy in response to a number of physiological and pathological stimuli. Calcineurin, a heterodimeric protein composed of a catalytic and a regulatory subunit, activates the nuclear factor NFATC4 which after translocation to the nucleus associates with the transcription factor GATA4 to activate several cardiac genes involved in hypertrophic response. We have screened the genes encoding the four major components of the heart calcineurin pathway in 95 individuals and identified 27 polymorphisms. These polymorphisms were investigated in 400 selected subjects obtained from a population-based study (LOVE) in relation to echocardiographic parameters. A Gly/Ala substitution at position 160 of the NFATC4 protein (G160A) was associated with left ventricular mass and wall thickness (P=0.02 and 0.006, respectively, GA+AA vs GG), the minor allele (Ala) being associated with lower mean values of these parameters. The other polymorphisms identified by the gene screen were not associated with cardiac phenotypes. For the G160A polymorphism in NFATC4, genotype frequencies were compared between patients with dilated cardiomyopathy and controls obtained from the CARDIGENE Study. Allele A carriers were less frequent in the patient than in the control group (P=0.04). Although the strength of the associations was rather weak, these observations raise the hypothesis that the G160A polymorphism of the NFATC4 gene plays a role in the development of human cardiac hypertrophy.
authors.affiliation: INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75634 Paris cedex 13, France.
authors.forename: Odette
authors.initials: O
authors.lastname: Poirier
authors.forename: Viviane
authors.initials: V
authors.lastname: Nicaud
authors.forename: Theresa
authors.initials: T
authors.lastname: McDonagh
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Dargie
authors.forename: Michel
authors.initials: M
authors.lastname: Desnos
authors.forename: Richard
authors.initials: R
authors.lastname: Dorent
authors.forename: Gérard
authors.initials: G
authors.lastname: Roizès
authors.forename: Ketty
authors.initials: K
authors.lastname: Schwartz
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: François
authors.initials: F
authors.lastname: Cambien
mesh_terms: D019703:Calcineurin / Q000235:genetics*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004452:Echocardiography; D050991:GATA4 Transcription Factor; D005820:Genetic Testing; D006801:Humans; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D019703:Calcineurin