Skarp Sini, Doedens Anne, Holmström Lauri, Izzi Valerio, Saarimäki Samu, Sliz Eeva, Kettunen Johannes, Pakanen Lasse, Kerkelä Risto, Pylkäs Katri, Huikuri Heikki V, Myerburg Robert J, Junttila Juhani
Research unit of Biomedicine and Internal Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
J Cardiovasc Transl Res. 2024 Dec;17(6):1229-1239. doi: 10.1007/s12265-024-10527-5. Epub 2024 Jun 7.
Myocardial fibrosis is a common finding in victims of sudden cardiac death (SCD). Whole exome sequencing was performed in 127 victims of SCD with primary myocardial fibrosis as the only pathological finding. These cases are derived from the Fingesture study which has collected data from autopsy-verified SCD victims in Northern Finland. A computational approach was used to identify protein interactions in cardiomyocytes. Associations of the identified variants with cardiac disease endpoints were investigated in the Finnish national genetic study (FinnGen) dataset. We identified 21 missense and one nonsense variant. Four variants were estimated to affect protein function, significantly associated with SCD/primary myocardial fibrosis (Fingesture) and associated with cardiac diseases in Finnish population (FinnGen). These variants locate in cartilage acidic protein 1 (CRATC1), calpain 1 (CAPN1), unc-45 myosin chaperone A (UNC45A) and unc-45 myosin chaperone B (UNC45B). The variants identified contribute to function of extracellular matrix and cardiomyocytes.
心肌纤维化是心源性猝死（SCD）患者的常见表现。对127例以原发性心肌纤维化为唯一病理表现的心源性猝死患者进行了全外显子组测序。这些病例来自Fingesture研究，该研究收集了芬兰北部经尸检证实的心源性猝死患者的数据。采用一种计算方法来识别心肌细胞中的蛋白质相互作用。在芬兰国家基因研究（FinnGen）数据集中研究了所识别变异与心脏疾病终点的关联。我们识别出21个错义变异和1个无义变异。估计有4个变异影响蛋白质功能，与SCD/原发性心肌纤维化（Fingesture）显著相关，并与芬兰人群中的心脏疾病（FinnGen）相关。这些变异位于软骨酸性蛋白1（CRATC1）、钙蛋白酶1（CAPN1）、unc-45肌球蛋白伴侣A（UNC45A）和unc-45肌球蛋白伴侣B（UNC45B）中。所识别的变异有助于细胞外基质和心肌细胞的功能。
