Abstract
Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with a 2-fold increased risk of mortality and a ~5- fold increased risk of stroke. Genome wide association studies have identified a locus on chromosome 4q25 that has the strongest association with AF. The SNPs in this locus most strongly associated with AF are located in an intergenic region that is 78 to 157 kb distal to the closest gene PITX2. PITX2 is a candidate gene for AF, due to its role in left/right patterning during heart development and expression found only in the left vs. right atrium. Our lab performed RNA-seq on human atria and identified a long intergenic non-coding RNA (linc-RNA) adjacent to PITX2 that is expressed with the same left/right atrial asymmetry as PITX2. We hypothesized that there may be functional genetic variants in the 4q25 region that directly affect expression of PITX2 or the linc-RNA adjacent to PITX2. Further, we hypothesized that the linc-RNA may control in trans the expression of genes that can alter cellular electrophysiology and lead to AF susceptibility. First we used qPCR to determine whether the expression of PITX2 and this linc-RNA were correlated in 199 human left atria samples. We found the expression of these genes to be highly and positively correlated with an r2 value of 0.47 (p < .0001). We obtained genome-wide SNP information for each of these subjects using an Illumina SNP microarray. We determined the association of SNPs on chromosome 4 with the expression levels of PITX2 and the linc-RNA by performing expression QTL (eQTL) analysis. In the 4q25 region, common genetic variation was more strongly associated with expression of the linc-RNA than PITX2. Two of the strongest linc-RNA eQTL SNPs (p-value ~10-4) were associated with AF with a p-value of ~10 15. We are now starting functional studies to determine if this linc-RNA can modulate gene expression in trans by transfection of a linc-RNA expression plasmid into HEK-293 cells. We plan to determine the effects of over expression this linc-RNA on global gene expression profiles using expression arrays and RNA-seq
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