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Causal SNP regulating FAM13B expression identified for the Chr. 5q31 atrial fibrillation susceptibility locus

Rationale Our prior RNA sequencing study found that FAM13B gene expression in human left atrial appendages was strongly associated with an atrial fibrillation (AF) susceptibility-associated variant on chr. 5q31. Objective To identify the common genetic variant responsible for regulating FAM13B expression and the effect of FAM13B expression on cardiomyocyte gene expression in order to gain insight into the functional mechanism of the chr. 5q31 AF susceptibility locus. Methods and Results By taking advantage of a smaller linkage disequilibrium block in African descent subjects and available chromatin conformation data, we identified the common single nucleotide polymorphism (SNP) rs17171731 as a candidate genetic variant controlling FAM13B gene expression in the left atrium. Functional analysis demonstrated that the AF risk allele of rs17171731 had less enhancer activity than the protective allele. Gel mobility shift studies determined that the risk allele bound to an additional protein that may function as a transcriptional repressor. Knockdown of FAM13B expression in stem cell-derived human cardiomyocytes (iCM) altered the expression of >1000 genes and modified the sodium current, consistent with increased susceptibility to atrial fibrillation. Transfection of GFP tagged FAM13B into iCMs demonstrated expression on the plasma membrane and at the Z-disk. Conclusions The chr. 5q31 AF risk variant was identified as rs17171731, with the risk allele having less enhancer activity, leading to decreased expression of FAM13B, which resides on the plasma membrane and the Z-disk, and appears to play a role in the regulation of cardiomyocyte gene expression and the late sodium current.