@entity460 Signaling Pathway Genes @entity8087 and XXXX Are Associated With Calcific Aortic Valve Disease.

@entity1 @entity8087 @entity18128 @entity4334 @entity8585 @entity460 @entity472
BACKGROUND: Calcific @entity472 ( @entity8585 ) is a life-threatening disease with no medical therapy. The genetic architecture of @entity8585 remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in @entity1 valve tissues to identify susceptibility genes of @entity8585 . METHODS AND RESULTS: A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 @entity8585 @entity1 . Twenty-five single- @entity4334 polymorphisms had P<5*10(-6) in the genome-wide association studies meta-analysis. The @entity460 signaling pathway was the top gene set enriched for genes mapped to moderately @entity8585 -associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without @entity8585 . Two single-nucleotide polymorphisms located in @entity8087 ( @entity8087 ), encoding an osteogenic transcription factor, demonstrated some association with @entity8585 (genome-wide association studies P=5.33*10(-5)). The mRNA expression levels of @entity8087 were upregulated in calcified valves and associated with eQTL-SNPs. @entity18128 encoding a subunit of a voltage-dependent @entity460 channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with @entity8585 located in @entity18128 was associated with higher expression of the gene. CONCLUSIONS: This integrative genomic study confirmed the role of @entity8087 as a potential driver of @entity8585 and identified a new @entity8585 susceptibility gene, @entity18128 , belonging to the @entity460 signaling pathway.
