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Decreased FAM13B Expression Increases Atrial Fibrillation Susceptibility by Regulating Sodium Current and
Gregory Tchou1, Daniela Ponce-Balbuena2, Nana Liu1
1Departments of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, Ohio, USA.
JACC. Basic to Translational Science
|December 14, 2023
Summary
A genetic variant linked to atrial fibrillation reduces FAM13B gene expression. This impacts cardiac function and increases arrhythmia susceptibility, suggesting FAM13B as a therapeutic target.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Atrial fibrillation (AF) is a common arrhythmia with complex genetic underpinnings.
- Identifying genetic variants that regulate gene expression is crucial for understanding disease mechanisms.
Purpose of the Study:
- To investigate the functional role of the genetic variant rs17171731 in atrial fibrillation (AF).
- To elucidate the downstream effects of altered FAM13B expression on cardiac function.
Main Methods:
- Utilized genetic association studies to identify the regulatory variant rs17171731.
- Performed gene knockdown experiments in stem cell-derived cardiomyocytes.
- Analyzed gene expression, ion channel function, and calcium (Ca2+) cycling.
- Generated and studied Fam13b knockout mouse models.
Main Results:
- The AF risk allele rs17171731 was confirmed as a regulatory variant controlling FAM13B expression.
- Reduced FAM13B expression led to altered expression of numerous genes, including SCN2B, in cardiomyocytes.
- These alterations resulted in pro-arrhythmogenic changes in late sodium current and Ca2+ cycling.
- Fam13b knockout mice exhibited prolonged P-wave and QT intervals and increased susceptibility to arrhythmias.
Conclusions:
- The genetic variant rs17171731 influences atrial fibrillation risk by modulating FAM13B expression.
- Dysregulation of FAM13B impacts cardiomyocyte function and promotes arrhythmias.
- FAM13B and its regulatory pathways represent potential targets for novel AF therapeutics.
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