Gene Expression Profiling: Identification of Novel Pathways and Potential Biomarkers in Severe Acute Pancreatitis.

ABSTRACT

BACKGROUND: Determining the risk of developing severe acute pancreatitis (AP) on presentation to hospital is difficult but vital to enable early management decisions that reduce morbidity and mortality. The objective of this study was to determine global gene expression profiles of patients with different acute pancreatitis severity to identify genes and molecular mechanisms involved in the pathogenesis of severe AP. STUDY DESIGN: AP patients (n = 87) were recruited within 24 hours of admission to the Emergency Department and were confirmed to exhibit at least 2 of the following features (1) abdominal pain characteristic of AP, (2) serum amylase and/or lipase more than 3-fold the upper laboratory limit considered normal, and/or (3) radiographically demonstrated AP on CT scan. Severity was defined according to the Revised Atlanta classification. Thirty-two healthy volunteers were also recruited and peripheral venous blood was collected for performing RNA-Seq. RESULTS: In severe AP, 422 genes (185 upregulated, 237 downregulated) were significantly differentially expressed when compared with moderately severe and mild cases. Pathway analysis revealed changes in specific innate and adaptive immune, sepsis-related, and surface modification pathways in severe AP. Data-driven approaches revealed distinct gene expression groups (endotypes), which were not entirely overlapping with the clinical Atlanta classification. Importantly, severe and moderately severe AP patients clustered away from healthy controls, whereas mild AP patients did not exhibit any clear separation, suggesting distinct underlying mechanisms that may influence severity of AP. CONCLUSION: There were significant differences in gene expression affecting the severity of AP, revealing a central role of specific immunological pathways. Despite the existence of patient endotypes, a 4-gene transcriptomic signature (S100A8, S100A9, MMP25, and MT-ND4L) was determined that can predict severe AP with an accuracy of 64%.