Atrial Fibrillation-Associated Locus 4Q25 Has the Cis-Regulatory Function toward the Neighboring Genes

概要

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Genome-wide association study (GWAS) of atrial fibrillation (AF) in Japanese population revealed that SNPs in 4q25 were strongly associated with AF. This region includes no protein-coding genes, but PITX2 exists in the neighborhood. Pitx2 is suggested for myocardial sleeve development in pulmonary vein and suppression of sinus node-like activities in left atrium, make us to assume that this gene-less regionmight include cis-regulatory elements toward neighboring genes such as PITX2. We tried to identify functional SNPs and to investigate pathogenesis of AF. We identified 155 variants including novel SNPs through re-sequencing the whole 4q25 region, selected 22 tag-SNPs, and analyzed association with AF. Among the 22 tag-SNPs, rs2200733 was the most strongly associated with AF. We regarded rs2200733 and other 22 SNPs in linkage disequilibrium as candidate functional SNPs. ChIPexperiments found that H3K4me1 and H3K27me3 bound to two specific SNPs, respectively. We performed reporter assay with reporter vectors, in which regions including each SNP were inserted with minimal promoter. We foundthesetwo regionselevated or suppressed transcriptional activities, respectively, and SNPs affected enhancement or suppression of transcriptional activities. These results demonstrate that cis-regulatory elements exist in 4q25 region and we assume that they control the expression of neighboring genes such as PITX2.