Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophages
IntroductionCardiac arrhythmia frequently co-presents with structural abnormalities such as cardiomyopathy and myocardial fibrosis, creating a bidirectional relationship where electrical disturbances and structural remodeling exacerbate each other. Current genetic studies focus on ion channel varian...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1611663/full |
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| author | Jie-Yuan Jin Jie-Yuan Jin Shuai Guo Yao Deng Ya-Qin Chen Chen Liang Yu-Jie Jiang Wang Zhao Rong Xiang |
| author_facet | Jie-Yuan Jin Jie-Yuan Jin Shuai Guo Yao Deng Ya-Qin Chen Chen Liang Yu-Jie Jiang Wang Zhao Rong Xiang |
| author_sort | Jie-Yuan Jin |
| collection | DOAJ |
| description | IntroductionCardiac arrhythmia frequently co-presents with structural abnormalities such as cardiomyopathy and myocardial fibrosis, creating a bidirectional relationship where electrical disturbances and structural remodeling exacerbate each other. Current genetic studies focus on ion channel variants, which explain part of the etiology. Molecular mechanisms underlying arrhythmias pathogenesis and its progression warrant further investigation.MethodsWe performed whole-exome sequencing on 50 arrhythmia patients (21 females, 29 males), predominantly with early-onset disease (94% ≤ 35 years). We focused on exonic deleterious mutations that are rare in healthy populations. The identified recurrently mutated (r.m.) genes were analyzed using protein-protein interaction networks and gene ontology enrichment for functional modules. These genomic insights were integrated with single-cell data (7 arrhythmias, 5 controls) to examine cell-type-specific gene expression changes, with particular focus on SPP1+ macrophage states.ResultsWe identified 132 r.m. genes present in ≥30% of patients in our cohort, with significant functional module enrichment in immune regulation, tissue homeostasis, extracellular matrix, and vesicle transport pathways. Single-cell analysis of 37,675 cells revealed conserved transcriptional signatures across cell types, characterized by enhanced cytokine responses and pro-fibrogenic programs. We discovered genetic determinants potentially underlying SPP1+ macrophage activation in arrhythmic hearts—a known mediator implicated in both inflammatory processes and fibrotic remodeling. Age-specific associations included ADAMTS7 mutations in very early-onset cases (≤20years; OR = 9.71 [2.38–47.74], P-value <0.001), while gender-specific variants included SLC9B1 (P-value = 0.017) exclusively in females. Additionally, OTOA mutations were associated with both relatively late onset (>20years; OR = 0.17 [0.04–0.68], P-value = 0.009) and female predominance (OR = 3.41 [0.92–13.58], P-value = 0.045).ConclusionOur exploratory analysis reveals how genetic variants may predispose arrhythmia patients to inflammatory and fibrotic processes. These findings may help guide future research into the molecular mechanisms underlying arrhythmia progression to structural heart disease and identify candidate pathways for therapeutic investigation. |
| format | Article |
| id | doaj-art-a5733d8a8ca24fd98866558621ce0ecb |
| institution | Kabale University |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-a5733d8a8ca24fd98866558621ce0ecb2025-08-20T04:03:12ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-08-011310.3389/fcell.2025.16116631611663Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophagesJie-Yuan Jin0Jie-Yuan Jin1Shuai Guo2Yao Deng3Ya-Qin Chen4Chen Liang5Yu-Jie Jiang6Wang Zhao7Rong Xiang8School of Medicine, Shaoxing University, Shaoxing, ChinaSchool of Life Sciences, Central South University, Changsha, ChinaSchool of Life Sciences, Central South University, Changsha, ChinaDepartment of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Cardiovascular Medicine, the Second Xiangya Hospital, Central South University, Changsha, ChinaCenter for Medical Genetics, Jiangmen Maternal & Child Healthcare Hospital, Jiangmen, ChinaSchool of Life Sciences, Central South University, Changsha, ChinaDepartment of Cardiovascular Medicine, the Second Xiangya Hospital, Central South University, Changsha, ChinaSchool of Life Sciences, Central South University, Changsha, ChinaIntroductionCardiac arrhythmia frequently co-presents with structural abnormalities such as cardiomyopathy and myocardial fibrosis, creating a bidirectional relationship where electrical disturbances and structural remodeling exacerbate each other. Current genetic studies focus on ion channel variants, which explain part of the etiology. Molecular mechanisms underlying arrhythmias pathogenesis and its progression warrant further investigation.MethodsWe performed whole-exome sequencing on 50 arrhythmia patients (21 females, 29 males), predominantly with early-onset disease (94% ≤ 35 years). We focused on exonic deleterious mutations that are rare in healthy populations. The identified recurrently mutated (r.m.) genes were analyzed using protein-protein interaction networks and gene ontology enrichment for functional modules. These genomic insights were integrated with single-cell data (7 arrhythmias, 5 controls) to examine cell-type-specific gene expression changes, with particular focus on SPP1+ macrophage states.ResultsWe identified 132 r.m. genes present in ≥30% of patients in our cohort, with significant functional module enrichment in immune regulation, tissue homeostasis, extracellular matrix, and vesicle transport pathways. Single-cell analysis of 37,675 cells revealed conserved transcriptional signatures across cell types, characterized by enhanced cytokine responses and pro-fibrogenic programs. We discovered genetic determinants potentially underlying SPP1+ macrophage activation in arrhythmic hearts—a known mediator implicated in both inflammatory processes and fibrotic remodeling. Age-specific associations included ADAMTS7 mutations in very early-onset cases (≤20years; OR = 9.71 [2.38–47.74], P-value <0.001), while gender-specific variants included SLC9B1 (P-value = 0.017) exclusively in females. Additionally, OTOA mutations were associated with both relatively late onset (>20years; OR = 0.17 [0.04–0.68], P-value = 0.009) and female predominance (OR = 3.41 [0.92–13.58], P-value = 0.045).ConclusionOur exploratory analysis reveals how genetic variants may predispose arrhythmia patients to inflammatory and fibrotic processes. These findings may help guide future research into the molecular mechanisms underlying arrhythmia progression to structural heart disease and identify candidate pathways for therapeutic investigation.https://www.frontiersin.org/articles/10.3389/fcell.2025.1611663/fullcardiac arrhythmiaswhole-exome sequencing (WES)single-cell transcriptomicsSPP1+ macrophageimmune dysregulationextracellular matrix remodeling |
| spellingShingle | Jie-Yuan Jin Jie-Yuan Jin Shuai Guo Yao Deng Ya-Qin Chen Chen Liang Yu-Jie Jiang Wang Zhao Rong Xiang Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophages Frontiers in Cell and Developmental Biology cardiac arrhythmias whole-exome sequencing (WES) single-cell transcriptomics SPP1+ macrophage immune dysregulation extracellular matrix remodeling |
| title | Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophages |
| title_full | Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophages |
| title_fullStr | Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophages |
| title_full_unstemmed | Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophages |
| title_short | Genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by SPP1+ macrophages |
| title_sort | genetic predisposition to immune dysregulation and extracellular matrix remodeling in cardiac arrhythmia reveals potential mediation by spp1 macrophages |
| topic | cardiac arrhythmias whole-exome sequencing (WES) single-cell transcriptomics SPP1+ macrophage immune dysregulation extracellular matrix remodeling |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1611663/full |
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