Abstract
In 2020, we discovered glycoprotein 2 (GP2) variants associated with pancreatic cancer susceptibility in a genome-wide association study involving the Japanese population. Individuals carrying a missense coding variant (rs78193826) in the GP2 gene resulting in a p.V432M substitution had an approximately 1.5-fold higher risk of developing pancreatic cancer than those without this variant. GP2 is expressed on the inner surface of zymogen granules in pancreatic acinar cells, which are responsible for the sorting, storage and secretion of digestive enzymes. Upon neuronal, hormonal, or other stimulation, GP2 is cleaved from the membrane of zymogen granules and then secreted into the pancreatic duct and intestinal lumen. While the functions of GP2 remain poorly understood, emerging evidence suggests that it plays an antibacterial role in the gastrointestinal tract after being secreted from pancreatic acinar cells. Impaired GP2 functions may facilitate the adhesion of bacteria to the intestinal mucosa. In this review article, we summarize the role of GP2 in health and disease, emphasizing its functions in the gastrointestinal tract, as well as genetic variations in the GP2 gene and their associations with disease susceptibility. We hope that its robust genetic associations with pancreatic cancer, coupled with its emerging role in gastrointestinal mucosal immunity, will spur renewed research interest in GP2, which has been understudied over the past 30 years compared with its paralog uromodulin (UMOD).
Highlights
Glycoprotein 2 (GP2) was isolated from granule membranes of the rat pancreas in 1990 [1]
In addition to replicating the majority of the genome-wide association study (GWAS) loci reported in European populations, we identified robust, relatively large effect-size associations of a coding missense variant in the GP2 gene with pancreatic cancer [4]
Impaired GP2 functions may facilitate the adhesion of bacteria to the intestinal mucosa
Summary
Glycoprotein 2 (GP2) was isolated from granule membranes of the rat pancreas in 1990 [1]. With a molecular mass of approximately 80 kDa, GP2 is expressed on the inner surface of zymogen granules of pancreatic acinar cells in various species [2]. Following the fusion of the membrane of zymogen granules (ZG) with the apical plasma membrane of pancreas acinar cells that is triggered by neuronal, hormonal, or other stimulation, GP2 is cleaved from the membrane of ZG and secreted into the pancreatic duct and intestinal lumen [3]. At least 23 susceptibility loci have been identified by GWASs involving individuals of European descent [7]. Whether these loci exist in non-European populations remains unknown, as minor allele frequencies
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