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<p>Aortic dissection (AD) is a life-threatening cardiovascular emergency in which delayed diagnosis and incomplete understanding of pathogenesis contribute to high mortality. To clarify the contribution of complement dysregulation to AD and to identify complement-related biomarkers with diagnostic and mechanistic relevance, we performed an integrative bioinformatics and clinical study focusing on C1q, C1r, and C1s. We identified four complement-related hub genes—C1R, C5, C9, and CFB—through differential gene expression analysis from GSE153434. C1R emerged as a key diagnostic marker with an area under the curve (AUC) of 88%, while Mendelian randomization revealed a causal relationship between genetically predicted C1R levels and AD incidence. Single-cell RNA sequencing revealed cell-type-specific expression patterns of C1r and C1s, highlighting their upregulation in smooth muscle cells and fibroblasts, indicating roles in vascular remodeling and extracellular matrix production. Serum C1q levels were significantly elevated in AD patients with a diagnostic threshold of 184.5&#xa0;mg/L and demonstrated moderate diagnostic performance (AUC = 0.795). However, Mendelian randomization (MR) provided no evidence for a causal role of genetically predicted C1q, suggesting that elevated C1q may reflect reactive immune/inflammatory responses rather than direct pathogenic mechanisms. Immunofluorescence localized C1r expression to smooth muscle cells in the aortic wall, corroborating its involvement in AD pathology. These findings elucidate the contributions of complement activation, particularly C1r and C1q, in AD pathogenesis. Our study underscores the diagnostic potential of complement-related biomarkers and suggests avenues for targeted therapeutic interventions. Taken together, these findings indicate that complement dysregulation is a central feature of AD and support C1r as a promising mechanistic and diagnostic marker, while elevated C1q represents a clinically informative, non-causal biomarker. Our findings highlight the complement system as a critical player in AD, offering new insights into its molecular role and potential as a therapeutic target.</p>

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Integrative bioinformatics reveals complement dysregulation: critical insights into C1q, C1r, and C1s in aortic dissection pathogenesis

  • 期刊论文

  • 发表日期：

    2026年3月10日

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  • Xiaoyu Wu,
  • Jinbao Qin,
  • Xin Wang,
  • Ruihua Wang,
  • Weimin Li,
  • Kun Liu,
  • Xinwu Lu

摘要

Aortic dissection (AD) is a life-threatening cardiovascular emergency in which delayed diagnosis and incomplete understanding of pathogenesis contribute to high mortality. To clarify the contribution of complement dysregulation to AD and to identify complement-related biomarkers with diagnostic and mechanistic relevance, we performed an integrative bioinformatics and clinical study focusing on C1q, C1r, and C1s. We identified four complement-related hub genes—C1R, C5, C9, and CFB—through differential gene expression analysis from GSE153434. C1R emerged as a key diagnostic marker with an area under the curve (AUC) of 88%, while Mendelian randomization revealed a causal relationship between genetically predicted C1R levels and AD incidence. Single-cell RNA sequencing revealed cell-type-specific expression patterns of C1r and C1s, highlighting their upregulation in smooth muscle cells and fibroblasts, indicating roles in vascular remodeling and extracellular matrix production. Serum C1q levels were significantly elevated in AD patients with a diagnostic threshold of 184.5 mg/L and demonstrated moderate diagnostic performance (AUC = 0.795). However, Mendelian randomization (MR) provided no evidence for a causal role of genetically predicted C1q, suggesting that elevated C1q may reflect reactive immune/inflammatory responses rather than direct pathogenic mechanisms. Immunofluorescence localized C1r expression to smooth muscle cells in the aortic wall, corroborating its involvement in AD pathology. These findings elucidate the contributions of complement activation, particularly C1r and C1q, in AD pathogenesis. Our study underscores the diagnostic potential of complement-related biomarkers and suggests avenues for targeted therapeutic interventions. Taken together, these findings indicate that complement dysregulation is a central feature of AD and support C1r as a promising mechanistic and diagnostic marker, while elevated C1q represents a clinically informative, non-causal biomarker. Our findings highlight the complement system as a critical player in AD, offering new insights into its molecular role and potential as a therapeutic target.