The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis

Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN Study Group

“…The remaining p.E79K variant, which was identified in a total of 17 patients with FCP, ICP or J o u r n a l P r e -p r o o f ACP in multiple studies [20], may be regarded as an outlier with respect to the GoF mechanism. The p.E79Kcationic trypsin was shown to transactivate PRSS2 (encoding anionic trypsinogen, the second major trypsinogen isoform after PRSS1) more efficiently than the wild-type [60]; a finding compatible with the growing view that increased PRSS2 expression acts as an independent GoF mechanism underlying CP [52]. In short, the clinical genetic, functional and population data concurred, supporting a "pathogenic" classification for all 17 variants.…”

“…It should however be emphasized that c.-204A>C may not be the sole functional variant underlying the increased risk of the c.-408T>C-tagged haplotype. This risk haplotype has been recently shown to contain the PRSS3P2 and TRY7 pseudogenes whereas the alternative haplotype has lost the two pseudogenes [50,51]; this alternative haplotype was reported to be associated with a protective effect against CP [52]. Interestingly, the risk haplotype appears to contain still functional PRSS3P2/TRY7 pseudogene enhancers that serve to upregulate pancreatic PRSS2 expression [53], which is consistent with the increasingly appreciated role of PRSS2 in J o u r n a l P r e -p r o o f pancreatitis (see Masson et al [52] and references therein).…”

“…This risk haplotype has been recently shown to contain the PRSS3P2 and TRY7 pseudogenes whereas the alternative haplotype has lost the two pseudogenes [50,51]; this alternative haplotype was reported to be associated with a protective effect against CP [52]. Interestingly, the risk haplotype appears to contain still functional PRSS3P2/TRY7 pseudogene enhancers that serve to upregulate pancreatic PRSS2 expression [53], which is consistent with the increasingly appreciated role of PRSS2 in J o u r n a l P r e -p r o o f pancreatitis (see Masson et al [52] and references therein). It is plausible that the risk conferred by the c.-408T>C-tagged haplotype is attributable to two non-mutually exclusive mechanisms.…”

Unravelling the role of gut microbiota in acute pancreatitis: integrating Mendelian randomization with a nested case–control study

“…These mechanisms include the regulation of gene transcription ( Liu et al, 2021 ), cell division ( Kee et al, 2012 ), cell signaling ( Perissinotti et al, 2014 ), fatty acylation ( Niu et al, 2019 ), immune modulation ( Wilson et al, 2012 ), cell membrane genesis ( Raghu et al, 2021 ), and protein degradation ( Castorena-Torres et al, 2008 ). Our detailed investigation of SNPs representing genetic susceptibility to AP ( Supplementary Table S3 ) revealed their association with digestive enzyme activity ( Bertin et al, 2023 ), cell signaling and cycle regulation ( Pelech and Sanghera, 1992 ), immune regulation and immune response ( Masson et al, 2023 ), cholesterol and plant steroid transport ( Yu et al, 2014 ), neural development and neural function ( de Castro-Catala et al, 2017 ), ion channels and regulation of cell excitability ( Al-Bataineh et al, 2023 ), cell adhesion and migration ( Camacho Leal et al, 2018 ), pancreatic function and trypsin regulation ( LaRusch et al, 2015 ), REDOX reactions, and cellular stress response ( Janda et al, 2015 ). Functional changes influenced by these SNPs may modulate the metabolism, growth, and interactions of microorganisms.…”