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Gehlen, Jan; Stundl, Anja; Debiec, Radoslaw; Fontana, Federica; Krane, Markus; Sharipova, Dinara; Nelson, Christopher P; Al-Kassou, Baravan; Giel, Ann-Sophie; Sinning, Jan-Malte; Bruenger, Christopher M H; Zelck, Carolin F; Koebbe, Laura L; Braund, Peter S; Webb, Thomas R; Hetherington, Simon; Ensminger, Stephan; Fujita, Buntaro; Mohamed, Salah A; Shrestha, Malakh; Krueger, Heike; Siepe, Matthias; Kari, Fabian Alexander; Nordbeck, Peter; [...]

Elucidation of the genetic causes of bicuspid aortic valve disease

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  • Medientyp: E-Artikel
  • Titel: Elucidation of the genetic causes of bicuspid aortic valve disease
  • Beteiligte: Gehlen, Jan; Stundl, Anja; Debiec, Radoslaw; Fontana, Federica; Krane, Markus; Sharipova, Dinara; Nelson, Christopher P; Al-Kassou, Baravan; Giel, Ann-Sophie; Sinning, Jan-Malte; Bruenger, Christopher M H; Zelck, Carolin F; Koebbe, Laura L; Braund, Peter S; Webb, Thomas R; Hetherington, Simon; Ensminger, Stephan; Fujita, Buntaro; Mohamed, Salah A; Shrestha, Malakh; Krueger, Heike; Siepe, Matthias; Kari, Fabian Alexander; Nordbeck, Peter; [...]
  • Erschienen: Oxford University Press (OUP), 2023
  • Erschienen in: Cardiovascular Research, 119 (2023) 3, Seite 857-866
  • Sprache: Englisch
  • DOI: 10.1093/cvr/cvac099
  • ISSN: 0008-6363; 1755-3245
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: Abstract Aims The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10−08) and was replicated in an independent case–control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10−16), GATA4 (P = 1.61 × 10−09), and TEX41 (P = 7.68 × 10−04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.
  • Zugangsstatus: Freier Zugang