| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Cardiovascular Research; Mar2023, Vol. 119 Issue 3, p857-866, 10p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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