# Whole exome sequencing reveals an FCGBP variant associated with spontaneous intraabdominal hemorrhage in severe acute pancreatitis

## TL;DR

A genetic variant in FCGBP is linked to spontaneous intraabdominal bleeding in severe pancreatitis, offering a new tool for early risk assessment and treatment.

## Contribution

Identification of a novel FCGBP gene variant associated with spontaneous intraabdominal hemorrhage in severe acute pancreatitis.

## Key findings

- A specific FCGBP variant (rs1326680184) is strongly associated with spontaneous intraabdominal hemorrhage in severe acute pancreatitis.
- Reduced FCGBP expression destabilizes vascular walls and exacerbates acute pancreatitis severity in mouse and human cell models.
- FCGBP mutation carriers show higher complication risks and worse prognosis, making it a valuable early diagnostic indicator.

## Abstract

This study investigated the genetic basis of spontaneous intraabdominal hemorrhage (SIH) in severe acute pancreatitis (SAP) to facilitate the development of more effective treatments for this life‐threatening complication. A four‐phase study was conducted with a large cohort of acute pancreatitis (AP) patients (n = 600). In the first phase, whole‐exome sequencing identified a specific exonic variant (rs1326680184) in the human Fc gamma binding protein (FCGBP) gene consistently associated with SIH. The second phase employed serum ELISA tests, revealing that this variant altered FCGBP protein levels, increasing susceptibility to SIH. In the third phase, functional validation was performed through: (i) in vivo experiments using a Fcgbp‐knockdown mouse model demonstrated that reduced Fcgbp expression exacerbated AP severity and increased the risk of hemorrhage; and (ii) in vitro experiments with FCGBP‐knockdown in human vascular fibroblasts showed that decreased FCGBP expression destabilized the vascular wall, leading to vascular injury in SAP. Finally, the fourth phase compared clinical characteristics of FCGBP rs1326680184 carriers and non‐carriers, finding that carriers exhibited higher risks of severe complications, worse AP prognosis, and demonstrated enhanced diagnostic utility as a predictive indicator. These findings provide critical insights into the genetic basis of SIH in SAP, paving the way for precision therapies and effective prognostic tools to improve AP management and early intervention.

A large cohort of acute pancreatitis patients (n = 600) underwent whole‐exome sequencing, which identified a genetic mutation in FCGBP strongly associated with a predisposition of spontaneous intraabdominal hemorrhage. Incorporating the FCGBP mutation as a clinical indicator enhances the assessment for complications and mortality risk in acute pancreatitis, even in the early phase of the disease.

A large cohort of acute pancreatitis patients (n = 600) underwent whole‐exome sequencing.Genetic mutation in FCGBP presents a strong association with the predisposition of spontaneous intraabdominal hemorrhage.The incorporation of FCGBP mutation as an indicator enhances the early assessment for complications and mortality of acute pancreatitis.

A large cohort of acute pancreatitis patients (n = 600) underwent whole‐exome sequencing.

Genetic mutation in FCGBP presents a strong association with the predisposition of spontaneous intraabdominal hemorrhage.

The incorporation of FCGBP mutation as an indicator enhances the early assessment for complications and mortality of acute pancreatitis.