Whole Exome Sequencing Reveals FCGBP Variant Associated with Spontaneous Intraabdominal Hemorrhage in Severe Acute Pancreatitis

Abstract

This study sought to identify genetic cause of spontaneous intraabdominal hemorrhage (SIH) in severe acute pancreatitis (SAP) to develop more effective treatment for this life-threatening complication. A four-phase study was conducted, leveraging a large-scale acute pancreatitis (AP) patients (n=600); the first phase involved whole-exome sequencing analyses, and identified specific exonic variant located in FCGBP (i.e., rs1326680184) that was consistently associated with SIH; the second phase performed serum ELISA tests, and revealed that FCGBP variant altered FCGBP level and further led to predisposition of SIH; the third phase conducted an i) in-vivo experiment with a Fcgbp-knockdown mouse model, and demonstrated lower expression of Fcgbp led to more severe AP morphology and higher risk of hemorrhage; ii) in-vitro experiment with FCGBP-knockdown human vascular fibroblasts demonstrated that down-regulated FCGBP expression could destabilize the vascular wall, and lead to vascular injury in SAP; the fourth phase compared FCGBP variant carriers to non-carriers with clinical characteristics, and found FCGBP variant associated with higher risks of poor complications and AP prognosis and enhanced the diagnostic capability as an indicator. These findings provide important insights into the underlying mechanism of SIH in SAP, and facilitate therapeutic development for AP prognosis and critical care in an early phase.