PUBLICATION
COMMD9-regulated endothelial cell abnormality-induced hypercoagulability is associated with Budd-Chiari syndrome
- Authors
- Gan, H., Li, J., Zheng, X., Hu, X., Yan, L., Li, B., Li, L., Zhou, B., Zu, M., Zhao, N., He, J., Wang, H., Tan, M., Li, W., Zhou, S., Zhang, J., Li, S., Xu, S., Zhao, L., Qi, X., Zhang, J., Xu, H., Pang, P.
- ID
- ZDB-PUB-260902-21
- Date
- 2026
- Source
- International journal of surgery (London, England) 112: 12728-12741 (Journal)
- Registered Authors
- Keywords
- Budd–Chiari syndrome, COMMD9, KLHDC2, endothelial cells, whole-exome sequencing
- MeSH Terms
- none
- PubMed
- 42682314 Full text @ Int J Surg
Citation
Gan, H., Li, J., Zheng, X., Hu, X., Yan, L., Li, B., Li, L., Zhou, B., Zu, M., Zhao, N., He, J., Wang, H., Tan, M., Li, W., Zhou, S., Zhang, J., Li, S., Xu, S., Zhao, L., Qi, X., Zhang, J., Xu, H., Pang, P. (2026) COMMD9-regulated endothelial cell abnormality-induced hypercoagulability is associated with Budd-Chiari syndrome. International journal of surgery (London, England). 112:12728-12741.
Abstract
Background Budd-Chiari syndrome (BCS) presents diagnostic and treatment challenges owing to its insidious onset. Genetic variants associated with BCS vary geographically; in Asian populations, the condition is primarily caused by membranous obstruction composed of endothelial cells (ECs). A better understanding of the genetic pathogenesis of membranous BCS may offer new insights into disease mechanisms.
Methods This study employed whole-exome sequencing to identify candidate genes responsible for EC abnormalities in 485 patients with membranous BCS and 329 patients with vascular malformations (VaMs). Functional investigations were conducted to validate the selected genes in vitro and in vivo.
Results Whole-exome data revealed that the frequency of variants in the vascular function-related KLHDC2 exceeded that of JAK2 in BCS. Knockdown of KLHDC2 promoted adhesion and suppressed proliferation of ECs. In addition, 92 genes enriched for rare variants overlapped between BCS and VaMs. Systems biology analysis revealed two gene clusters, including COMMD9, enriched in proteins intolerant to loss-of-function mutations. Furthermore, suppression of COMMD9 impaired EC migration and tube formation, inhibited subintestinal angiogenic sprouting in zebrafish, and elevated EC adhesion. Transcriptomic analysis linked COMMD9 to EC abnormalities via the PI3K-Akt pathway. Commd9 knockdown promoted venous hypercoagulability in vivo following drug or ligation-induced stenosis.
Conclusions These findings indicate that multiple rare genetic variants, particularly in COMMD9, are involved in the development of membranous BCS by regulating hypercoagulability induced by EC abnormalities. These findings may help guide future clinical research towards improved understanding and treatment of BCS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping