Decreased FAM13B expression increases atrial fibrillation susceptibility by regulating sodium current and calcium handling

Objectives: To determine the causal genetic variant and gene and the
mechanism for the atrial fibrillation (AF) genome wide association study
(GWAS) locus on chromosome 5q31.
Background: FAM13B expression is strongly associated
with the lead AF GWAS variant at 5q31.  However, the
regulatory variant controlling FAM13B expression and the
mechanism by which FAM13B impacts AF susceptibility are
not known. Methods: Bioinformatics, reporter gene transfections, gel
shifts, and gene editing were used to identify the variant
regulating FAM13B expression. RNAseq
after FAM13B knockdown in stem cell-derived
cardiomyocytes (iCMs) identified downstream processes. Patch clamp and
calcium transient assays were used to assess downstream
mechanisms. Fam13b knockout (KO) mice were studied for heart
structural and functional changes, and pacing-induced arrhythmia. Results:
rs17171731 was identified as the regulatory variant
controlling FAM13B expression, with decreased enhancer
activity of the risk allele.  Knockdown
of FAM13B in iCMs altered expression of >1000
genes including SCN2B and led to pro-arrhythmogenic
changes in the late sodium current and
Ca2+ cycling.  FAM13B is a member of
the Rho GTPase-activating protein (RhoGAP) gene family, but failed to
demonstrate RhoGAP activity.  GFP-tagged FAM13B
expressed in iCMs localized at the Z-disc and plasma membrane.
Fam13b knockout mice had increased basal p-wave duration and QT
interval, and were more susceptible to pacing-induced arrhythmias vs.
controls. Conclusions: This study went from an AF GWAS locus to identify
the causal variant and gene, mechanisms for this association, and
confirmed arrhythmia susceptibility in Fam13b KO
mice. FAM13B and downstream effectors are potential targets for
patient-specific therapeutics.