Abstract 8221: Cis Regulation of Genes in Human Atria Near SNPs Associated with Atrial Fibrillation and PR Interval
Genome-wide association studies have identified genetic variants in 3 regions associated with atrial fibrillation (AF) and in 9 regions associated with PR interval (PR), an AF-related endophenotype. The mechanisms linking these top variants to the AF phenotype remain unknown. Our study aimed to elucidate these mechanisms by associating SNP genotypes in the 12 implicated regions with proximal (cis) gene expression in human left atria (LA) and by examining differential expression of cis genes with atrial rhythm status at time of surgery.
METHODS: Gene expression (Illumina HT12) and SNP genotypes (Illumina Hap550/610) were measured on LA appendages from 234 cardiac surgery patients. Expression and genotypes were preprocessed using best practices. Probes for the 15 genes closest to the top AF and PR-associated SNPs were adjusted for gender, age, genetic stratification and latent expression factors then regressed on their corresponding cis SNP dosage counts to obtain expression quantitative trait SNP (eSNP) p-values. Similar adjustments were done to obtain differential expression p-values.
RESULTS: 7 significant eSNPs were found from 14 AF/PR SNPs: rs10033464 (p=0.033) and rs17570669 (9.9e-3) with PITX2, rs13376333 with KCNN3 (0.046), rs3807989 with CAV1 (4.9e-9), rs11897119 with MEIS1 (2.2e-5), rs427684 with C5orf41 (4.6e-4), rs3825214 with TBX5 (5.0e-3), with rs7660702 marginal for ARHGAP24 (0.077). rs3807989 and rs11897119 were the strongest among all SNPs within 500 KB of their target gene. 8 out of 13 cis genes showed significant differential expression between the No AF (n=38) and AF Rhythm groups (n=100) or between the AF/In Sinus Rhythm (n=100) and AF Rhythm groups, respectively, with 3 showing both: CAV1 (2.1e-3,7.0e-11), TBX5 (0.015,NS), PITX2 (0.015,NS), BNIP1 (0.023,0.026), ARHGAP24 (0.029,2.4e-7), ZFHX3 (0.053,NS), CAV2 (NS,7.1e-3) and C5orf41 (NS,0.025).
CONCLUSIONS: We have provided evidence that many of the SNPs associated with AF and PR also associate with expression levels of nearby genes in human left atria and that these genes are differentially expressed in AF.
- © 2011 by American Heart Association, Inc.