Whole Exome Sequencing RevealsFCGBPVariant Associated with Spontaneous Intraabdominal Hemorrhage in Severe Acute Pancreatitis

Abstract

AbstractThis 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 inFCGBP(i.e., rs1326680184) that was consistently associated with SIH; the second phase performed serum ELISA tests, and revealed thatFCGBPvariant altered FCGBP level and further led to predisposition of SIH; the third phase conducted an i)in-vivoexperiment with aFcgbp-knockdown mouse model, and demonstrated lower expression ofFcgbpled to more severe AP morphology and higher risk of hemorrhage; ii)in-vitroexperiment withFCGBP-knockdown human vascular fibroblasts demonstrated that down-regulatedFCGBPexpression could destabilize the vascular wall, and lead to vascular injury in SAP; the fourth phase comparedFCGBPvariant carriers to non-carriers with clinical characteristics, and foundFCGBPvariant 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.HighlightsGenetic mutation inFCGBPpresents a strong association with predisposition of spontaneous intraabdominal hemorrhage, and provide a novel insight in increasing the severity of acute pancreatitis when knockdown the expression of Fcgbp.The incorporation ofFCGBPmutation as an indicator enhances the ability of clinical assessment with respect to complications and mortality of acute pancreatitis in an early phase before manifestation.Our findings highlight the geneFCGBPas a probable pathogenic cause of spontaneous intraabdominal hemorrhage in severe acute pancreatitis patients, which enable a development of effective targeted therapies in improving the prognosis and critical care of severe acute pancreatitis.