Abstract | BACKGROUND:
Atrial fibrillation (AF) is the most common cardiac arrhythmia; however, the current treatment strategies for AF have limited efficacy. Thus, a better understanding of the mechanisms underlying AF is important for future therapeutic strategy. A previous study (Exome-Wide Association Study (ExWAS)) identified a rare variant, rs202011870 (MAF=0.00036, GenomAD), which is highly associated with AF (OR=3.617, P<0.0001). rs202011870 results in the replacement of Leu at 396 with Arg (L396R) in a molecule, Tks5; however, the mechanism of how rs202011870 links to AF is completely unknown.Methods and Results:The association of rs202011870 with AF was examined in 3,378 participants (641 control and 2,737 AF cases) from 4 independent cohorts by using an Invader assay. Consequences of rs202011870 in migration ability, podosome formation, and expression of inflammation-related molecules in macrophages were examined using RAW264.7 cells with a trans-well assay, immunocytochemistry, and qPCR assay. Validation of the association of rs202011870 with AF was successful. In vitro studies showed that RAW264.7 cells with L396R-Tks5 increased trans-well migration ability, and enhanced podosome formation. RAW264.7 cells with L396R-Tks5 also increased the expression of several inflammatory cytokines and inflammation-related molecules. CONCLUSIONS: L396R mutation in Tks5 associated with AF enhances migration of macrophages and their inflammatory features, resulting in enhanced susceptibility to AF.
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Authors | Xiaoxi Yang, Tetsuo Sasano, Yusuke Ebana, Jun K Takeuchi, Kensuke Ihara, Masahiro Yamazoe, Tetsushi Furukawa |
Journal | Circulation journal : official journal of the Japanese Circulation Society
(Circ J)
Vol. 84
Issue 12
Pg. 2148-2157
(11 25 2020)
ISSN: 1347-4820 [Electronic] Japan |
PMID | 33087629
(Publication Type: Journal Article)
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Chemical References |
- Adaptor Proteins, Vesicular Transport
- SH3PXD2A protein, human
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Topics |
- Adaptor Proteins, Vesicular Transport
(genetics)
- Animals
- Atrial Fibrillation
(genetics)
- Cell Movement
- Exome
- Humans
- Inflammation
- Mice
- Mutation
- RAW 264.7 Cells
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