title: Identification of Gender-Specific Genetic Variants in Patients With Bicuspid Aortic Valve.
abstract: Bicuspid aortic valve (BAV) is the most frequent congenital heart defect and has a male predominance of 3 to 1. A large proportion of patients develop valvular and aortic complications. Despite the high prevalence of BAV, its cause and genetic origins remain elusive. The goal of this study was to identify genetic variants associated with BAV. Nine genes previously associated with BAV (NOTCH1, AXIN1, EGFR, ENG, GATA5, NKX2-5, NOS3, PDIA2, and TGFBR2) were sequenced in 48 patients with BAV using the Ion Torrent Personal Genome Machine. Pathogenicity of genetic variants was evaluated with the Combined Annotation Dependent Depletion framework. A selection of 89 variants identified by sequencing or in previous BAV genetic studies was genotyped, and allele frequencies were compared in 323 patients with BAV confirmed at surgery and 584 controls. Analyses were also performed by gender. Nine novel and 19 potentially pathogenic variants were identified by next-generation sequencing and confirmed by Sanger sequencing, but they were not associated with BAV in the case-control population. A significant association was observed between an in silico-predicted benign EGFR intronic variant (rs17290301) and BAV. Analyses performed by gender revealed different variants associated with BAV in men (EGFR rs533525993 and TEX26 rs12857479) and women (NOTCH1 rs61751489, TGFBR2 rs1155705, and NKX2-5 rs2277923). In conclusion, these results constitute the first association between EGFR genetic variants and BAV in humans and support a possible role of gender-specific polymorphisms in the development of BAV.
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Dargis
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lamontagne
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Sbarra
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada.
authors.forename: Cyndi
authors.initials: C
authors.lastname: Henry
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Quebec City, Quebec, Canada; Department of Molecular Medicine, Laval University, Quebec City, Quebec, Canada. Electronic address: yohan.bosse@criucpq.ulaval.ca.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000002:abnormalities* / Q000000981:diagnostic imaging; D000082882:Bicuspid Aortic Valve Disease; D004247:DNA / Q000235:genetics*; D004452:Echocardiography; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006349:Heart Valve Diseases / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011792:Quebec / Q000453:epidemiology; D012720:Severity of Illness Index; D017678:Sex Distribution; D012737:Sex Factors
chemical_list: D004247:DNA