Chronic pancreatitis is an inflammatory disorder of the pancreas. We analyzed CPA1 encoding carboxypeptidase A1 in subjects with non-alcoholic chronic pancreatitis and controls in a German discovery cohort and three replication cohorts. Functionally impaired variants were present in 29/944 (3.1%) German patients and in 5/3,938 (0.1%) controls (odds ratio [OR] = 24.9; P = 1.5 × 10-16). The association was strongest in subjects aged ≤10 years (9.7%; OR = 84.0; P = 4.1 × 10-24). In the replication cohorts, defective CPA1 variants were observed in 8/600 (1.3%) patients and in 9/2,432 (0.4%) controls from Europe (P = 0.01), in 5/230 (2.2%) patients and 0/264 controls from India (P = 0.02), and in 5/247 (2.0%) patients but 0/341 controls from Japan (P = 0.013). The mechanism of increased pancreatitis risk by CPA1 variants may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity as seen with other genetic risk factors.

The oxytocin system has a crucial role in human sociality; several results prove that polymorphisms of the oxytocin receptor gene are related to complex social behaviors in humans. Dogs' parallel evolution with humans and their adaptation to the human environment has made them a useful species to model human social interactions. Previous research indicates that dogs are eligible models for behavioral genetic research, as well. Based on these previous findings, our research investigated associations between human directed social behaviors and two newly described (−212AG, 19131AG) and one known (rs8679684) single nucleotide polymorphisms (SNPs) in the regulatory regions (5′ and 3′ UTR) of the oxytocin receptor gene in German Shepherd (N = 104) and Border Collie (N = 103) dogs. Dogs' behavior traits have been estimated in a newly developed test series consisting of five episodes: Greeting by a stranger, Separation from the owner, Problem solving, Threatening approach, Hiding of the owner. Buccal samples were collected and DNA was isolated using standard protocols. SNPs in the 3′ and 5′ UTR regions were analyzed by polymerase chain reaction based techniques followed by subsequent electrophoresis analysis. The gene–behavior association analysis suggests that oxytocin receptor gene polymorphisms have an impact in both breeds on (i) proximity seeking towards an unfamiliar person, as well as their owner, and on (ii) how friendly dogs behave towards strangers, although the mediating molecular regulatory mechanisms are yet unknown. Based on these results, we conclude that similarly to humans, the social behavior of dogs towards humans is influenced by the oxytocin system.

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The pancreas secretes digestive proenzymes typically in their monomeric form. A notable exception is the ternary complex formed by proproteinase E, chymotrypsinogen C, and procarboxypeptidase A (proCPA) in cattle and other ruminants. In the human and pig pancreas binary complexes of proCPA with proelastases were found. To characterize complex formation among human pancreatic protease zymogens in a systematic manner, we performed binding experiments using recombinant proelastases CELA2A, CELA3A, and CELA3B; chymotrypsinogens CTRB1, CTRB2, CTRC, and CTRL1; and procarboxypeptidases CPA1, CPA2, and CPB1. We found that proCELA3B bound not only to proCPA1 (K D 43 nM) but even more tightly to proCPA2 (K D 18 nM), whereas proCELA2A bound weakly to proCPA1 only (K D 152 nM). Surprisingly, proCELA3A, which shares 92% identity with proCELA3B, did not form stable complexes due to the evolutionary replacement of Ala 241 with Gly. The polymorphic nature of position 241 in both CELA3A (ϳ4% Ala 241 alleles) and CELA3B (ϳ2% Gly 241 alleles) points to individual variations in complex formation. The functional effect of complex formation was delayed procarboxypeptidase activation due to increased affinity of the inhibitory activation peptide, whereas proelastase activation was unchanged. We conclude that complex formation among human pancreatic protease zymogens is limited to a subset of proelastases and procarboxypeptidases. Complex formation stabilizes the inhibitory activation peptide of procarboxypeptidases and thereby increases zymogen stability and controls activation.The exocrine pancreas produces digestive enzymes including serine-and metalloproteases secreted as inactive precursors (zymogens) that attain their active form in the duodenum. Physiological activation of protease zymogens is initiated by enteropeptidase-mediated activation of trypsinogen to trypsin followed by trypsin-mediated activation of chymotrypsinogens, proelastases, and procarboxypeptidases (1). Full activation of human procarboxypeptidases A1 (proCPA1) 2 and A2 (proCPA2) requires additional cleavages by chymotrypsin C (CTRC) to facilitate dissociation of the inhibitory activation peptide (2). Renewed interest in digestive protease physiology was spurred by the recognition that mutations in cationic trypsinogen (PRSS1), the pancreatic secretory trypsin inhibitor (SPINK1), CTRC and CPA1 are strongly associated with chronic pancreatitis in humans (3-6). At the same time, information obtained from genome and pancreatic transcriptome sequencing allowed correct annotation of the full complement of digestive protease isoforms and opened up avenues for investigations using genetically-defined recombinant enzymes. These studies, in turn, led to novel insight into digestive protease function such as the central role of CTRC in the regulation of human trypsinogen (7-9) and procarboxypeptidase activation (2), the role of mesotrypsin (PRSS3) in degrading trypsin inhibitors (10, 11), and the significance of mutation-induced digestive protease misfolding in acinar ce...