The Heart Valve Society

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Protein-Altering and Regulatory Genetic Variants Near GATA4 Implicated in Bicuspid Aortic Valve
Bo Yang1, Wei Zhou1, Jiao Jiao1, Jonas Nielsen1, Michael Mathis1, Mahyar Heydarpour2, Guillaume Lettre3, Lasse Folkersen4, Siddharth Prakash5, Claudia Schurmann6, Maoxuan Lin1, Mohammad Othman1, Jacob Kitzman1, Alan Boyle1, Santhi Ganesh1, Gonçalo Abecasis1, Kim Eagle1, Ruth J.F. Loos6, Per Eriksson4, Jean-Claude Tardif3, Chad M. Brummett1, Dianna Milewicz5, Simon Body2, Cristen Willer1.
1University of Michigan, Ann Arbor, MI, USA, 2Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 3Université de Montréal, Montreal, QC, Canada, 4Karolinksa University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, 5University of Texas Health Science Center at Houston, Houston, TX, USA, 6The Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Bicuspid aortic valve (BAV) disease is a heritable congenital heart defect. The genetic variants associated with non-syndromic BAV are largely unknown. Individuals born with BAV have substantially increased risk of aortic stenosis and incompetence, and aortic aneurysm. Methods: To identify the underlying causes of BAV, we performed genome-wide association testing of 466 BAV cases and 4,660 age, sex, and ethnicity-matched controls with replication in an additional 1,360 cases and 8,205 controls. A potential causal gene was interrupted by CRISPR Cas9 and single guide RNA (sgRNA) in induced pleuripotent stem cells (iPSCs) from donors with normal tri-leaflet aortic valve. In iPSCs with and without gene editing, the migration and mesenchymal transition of endothelial cells were measured by collagen gel assay and expression of CD31 and smooth muscle actin was determined. Results: We identified association with a non-coding variant (rs6601627, OR = 1.90, 95% CI 1.62 - 2.23, p=3x10-15) 151kb from the cardiac-specific transcription factor, GATA4, and near-significance for protein-altering p.Ser377Gly in GATA4 (rs3729856, OR = 1.31, 95% CI 1.19 - 1.45, p=1x10-7). These variants were determined to be independent from each other by conditional analysis. This locus allowed investigation of both protein-coding and non-coding regulation of an important cardiac transcription factor and its involvement in a congenital heart defect. We identified chromatin interaction loops in K562, using ChIA-PET data and Hi-C data, between associated variants and a region in the large 40kb intron of GATA4. The disruption of GATA4 significantly impaired the migration of endothelial cells and also transition from endothelial cells into mesenchymal cells, a critical step in heart valve development. Conclusion: We identified association of BAV with a low frequency non-coding variant 151kb from GATA4, as well as a common missense variant in GATA4 that is critical for the aortic valve development.


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