Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.
Bo YangWei ZhouJiao JiaoJonas Bille NielsenMichael R MathisMahyar HeydarpourGuillaume LettreLasse FolkersenSiddharth PrakashClaudia SchurmannLars G FritscheGregory A FarnumMaoxuan LinMohammad OthmanWhitney HornsbyAnisa DriscollAlexandra LevasseurMarc ThomasLinda FarhatMarie-Pierre DubéEric M IsselbacherAnders Franco-CerecedaDong-Chuan GuoErwin P BottingerG Michael DeebAnna BooherSachin KheterpalY Eugene ChenHyun Min KangJacob KitzmanHeather J CordellBernard D KeavneyJudith A GoodshipSanthi K GaneshGonçalo AbecasisKim A EagleAlan P BoyleRuth J F LoosPer ErikssonJean-Claude TardifChad M BrummettDianna M MilewiczSimon C BodyCristen J WillerPublished in: Nature communications (2017)
Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.
Keyphrases
- aortic valve
- transcription factor
- aortic stenosis
- transcatheter aortic valve replacement
- transcatheter aortic valve implantation
- aortic valve replacement
- crispr cas
- genome wide identification
- dna binding
- induced pluripotent stem cells
- endothelial cells
- genome wide association
- genome editing
- induced apoptosis
- stem cells
- bone marrow
- computed tomography
- ejection fraction
- cell cycle arrest
- dna methylation
- coronary artery disease
- copy number
- binding protein
- gene expression
- signaling pathway
- magnetic resonance
- protein protein
- small molecule
- mitral valve
- contrast enhanced