Genome-wide discovery of enhancer - promoter interactions in the human pancreas using an improved Activity-By-Contact-based model.

Background/objectives: Enhancers are key drivers of tissue-specific gene expression and can contain variants associated with pancreatic diseases. Enhancer-target gene assignment remains challenging, with the Activity-By-Contact (ABC) model, integrating open-chromatin, histone modification and chromatin interaction data, consistently outperforming other approaches. Recently an advanced version, the generalized ABC (gABC) model was published, yet lacking a clear and unique promoter definition impairing interpretability.

Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis.

The CEL-HYB1 hybrid allele of the carboxyl ester lipase (CEL) gene and its pseudogene (CELP) has been associated with chronic pancreatitis (CP). Recent work indicated that amino acid positions 488 and 548 in CEL-HYB1 determined pathogenicity. Haplotype Thr488-Ile548 was associated with CP while haplotypes Thr488-Thr548 and Ile488-Thr548 were benign.

Loss-of-function variant in chymotrypsin like elastase 3B (CELA3B) is associated with non-alcoholic chronic pancreatitis.

Background: Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP.

Risk of chronic pancreatitis in carriers of loss-of-function CTRC variants: A meta-analysis.

The digestive protease chymotrypsin C (CTRC) protects the pancreas against pancreatitis by degrading potentially harmful trypsinogen. Loss-of-function genetic variants in CTRC increase risk for chronic pancreatitis (CP) with variable effect size, as judged by the reported odds ratio (OR) values. Here, we performed a meta-analysis of published studies on four variants that alter the CTRC amino-acid sequence, are clinically relatively common (global carrier frequency in CP >1%), reproducibly showed association with CP and their loss of function phenotype was verified experimentally.

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.

Background: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions.

Methods: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants.

[Pathogenesis of chronic pancreatitis].

Long-term alcohol consumption and gene mutations are the most important causes of chronic pancreatitis. In addition to mutations in acinar genes, such as digestive enzymes and their inhibitors, defects in genes that primarily or exclusively affect the duct cells have also been described in recent years. Genetic changes are found not only in patients with a positive family history (hereditary pancreatitis) but also in so-called idiopathic and, to a lesser extent, in alcoholic chronic pancreatitis.

The three common polymorphisms p.A986S, p.R990G and p.Q1011E in the calcium sensing receptor (CASR) are not associated with chronic pancreatitis.

Background: The calcium sensing receptor (CASR) is a G protein-coupled receptor that is responsible for assessing extracellular Ca levels and thus plays a crucial role in calcium homeostasis. Hypercalcemia is a metabolic risk factor for pancreatitis and rare CASR variants have been described in patients with chronic pancreatitis. At the carboxy-terminal tail of CASR, there is a cluster of three common polymorphisms, p.

Sequencing of the complex CTRB1-CTRB2 locus in chronic pancreatitis.

Background: /Objectives: A recent Genome-wide Association Study (GWAS) in alcoholic chronic pancreatitis (ACP) identified a novel association with the CTRB1-CTRB2 (chymotrypsinogen B1, B2) locus, linked to a 16.6 kb inversion that was confirmed in non-alcoholic chronic pancreatitis (NACP). Moreover, recent findings on the function of CTRB1 and CTRB2 suggest a protective role in pancreatitis development.

Analysis of GPRC6A variants in different pancreatitis etiologies.

Background: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis.

Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.

Background & Aims: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca-selective ion channel, in an international cohort of patients and in mice.

Methods: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP.

Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis.

Objectives: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene.

IRF5 Is Required for Bacterial Clearance in Human M1-Polarized Macrophages, and Immune-Mediated Disease Risk Variants Modulate This Outcome.

Common IFN regulatory factor 5 () variants associated with multiple immune-mediated diseases are a major determinant of interindividual variability in pattern recognition receptor (PRR)-induced cytokines in macrophages. PRR-initiated pathways also contribute to bacterial clearance, and dysregulation of bacterial clearance can contribute to immune-mediated diseases. However, the role of IRF5 in macrophage-mediated bacterial clearance is not well defined.

Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis.

Background/objectives: Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic pancreatitis (CP) few robust genetic associations have been described.