論文 - 詳細
| RRC ID | 63131 |
|---|---|
| 著者 | Yang X, Sasano T, Ebana Y, Takeuchi JK, Ihara K, Yamazoe M, Furukawa T. |
| タイトル | Functional Role of the L396R Mutation of Tks5 Identified by an Exome-Wide Association Study in Atrial Fibrillation. |
| ジャーナル | Circ J |
| 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. |
| 巻・号 | 84(12) |
| ページ | 2148-2157 |
| 公開日 | 2020-11-25 |
| DOI | 10.1253/circj.CJ-20-0101 |
| PMID | 33087629 |
| MeSH | Adaptor Proteins, Vesicular Transport / genetics* Animals Atrial Fibrillation* / genetics Cell Movement Exome* Humans Inflammation Mice Mutation RAW 264.7 Cells |
| IF | 2.54 |
| リソース情報 | |
| ヒト・動物細胞 | RAW 264(RCB0535) |