The Developmental Regulation of Bicuspid Aortic Valve as Marker to its Presentation in the Adult

Bicuspid aortic valve (BAV) is the most common congenital heart malformation with a prevalence of 0.5-2% in the general population. BAV refers to the fusion of two out of the three leaflets that form the aortic valve, which affects blood flow hemodynamics. BAV has a complex heredity. Our hypothesis is that regulatory elements expressed in the developing heart contribute to the trait. Here we show computationally the possibility that specific combinations of variants contribute to malformation in regulatory elements and play part in BAV formation. Past studies show that variants inside regulatory sequences appear to additively affect the expression of target genes.

Our data includes 480 BAV patients’ genome wide SNPs (OMNI-2.5). We focused on enhancers proven to be active during heart development (enhancer.lbl.gov). We prioritized a list based on the number of SNPs with MAF>0.3 inside enhancers. To further narrow down the list more restrictions were imposed such as the evolutionary stress. We analyzed the frequency of SNP combinations that may seemingly be working together. Using ‘apriori’ we listed the association rules in a representative 5kb enhancer, “mm18”, and found a robust association rule of 3 SNP’s that covers 35% of the cases . The enhancer “mm18” serves as a template for capturing “collaborating” variants. In the future we will work out a systematic plan to expand to greater genomic scales for full exploitation of this method’s potential. This also requires a larger cohort of BAV cases/controls. To this end a release of a 6,000-patient data-bank (BAVCon) is pending authorization.