ABSTRACT
Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P = .0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P = .087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P = .0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer.
Subject(s)
Carboxypeptidase B/genetics , Carboxypeptidases A/genetics , Carcinoma, Pancreatic Ductal/etiology , Endoplasmic Reticulum Stress/physiology , Pancreatic Neoplasms/etiology , Carboxypeptidase B/physiology , Carboxypeptidases A/physiology , Carcinoma, Pancreatic Ductal/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genetic Variation , Humans , Pancreatic Neoplasms/genetics , RiskABSTRACT
The coagulation and fibrinolytic systems safeguard the patency of the vasculature and surrounding tissue. Cross regulation of coagulation and fibrinolysis plays an important role in preserving a balanced hemostatic process. Identification of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) as an inhibitor of fibrinolysis and one of the main intermediates between coagulation and fibrinolysis, greatly improved our understanding of cross regulation of coagulation and fibrinolysis. As TAFI is an enzyme that is activated by thrombin generated by the coagulation system, its activation is sensitive to the dynamics of the coagulation system. Defects in coagulation, such as in thrombosis or hemophilia, resonate in TAFI-mediated regulation of fibrinolysis and imply that clinical symptoms of coagulation defects are amplified by unbalanced fibrinolysis. Thrombomodulin promotes the generation of both antithrombotic activated protein C (APC) and prothrombotic (antifibrinolytic) activated TAFI, illustrating the paradoxical effects of thrombomodulin on the regulation of coagulation and fibrinolysis. This review will discuss the role of TAFI in the regulation of fibrinolysis and detail its regulation of activation and its potential therapeutic applications in thrombotic disease and bleeding disorders.
Subject(s)
Carboxypeptidase B2/physiology , Carboxypeptidase B/chemistry , Carboxypeptidase B/physiology , Fibrinolysis/physiology , Animals , Antifibrinolytic Agents/therapeutic use , Blood Coagulation/physiology , Carboxypeptidase B/antagonists & inhibitors , Carboxypeptidase B2/genetics , Carboxypeptidase B2/therapeutic use , Enzyme Stability , Genetic Engineering/methods , Genetic Engineering/trends , Genetic Variation , Hemophilia A/drug therapy , Humans , Thrombin/physiology , Thrombolytic Therapy , Thrombomodulin/physiologyABSTRACT
The paper is devoted to analysis of the literature data about a recently described component of haemostasis system that posseses carboxypeptidase activity and is activated by thrombin. The history of investigation and isolation of the new carboxypeptidase, their properties and participation in inhibition of fibrinolysis reactions was considered. Data are cited about carboxypeptidase B level changes under different physiological conditions and possible methods of fibrinolysis reactions strengthening by means of influence on activity of that carboxypeptidase.
