New horizons in pancreatic genetics.

PURPOSE OF REVIEW: Pancreatitis remains an intractable disease because no causative treatment is yet available. Recent studies have uncovered some of its underlying pathophysiology, a requirement for identifying potential treatment targets. These advancements were achieved by human genetic studies and by introducing genetic mechanisms into experimental pancreatitis models. RECENT FINDINGS: Cationic trypsin mutations are the most prominent genetic risk factor for pancreatitis. Investigators have now introduced genetically modified trypsin variants into transgenic animals. In this manner they characterized the role of cellular defense mechanisms, for example degradation of active trypsin by chymotrypsin-C, but also found that increased autoactivation or decreased degradation, not only boost disease severity but also drive progression to chonic pancreatitis. Other studies found that harmful trypsin effects are not restricted to acinar cells, that other digestive enzymes, notably pancreatic elastase, can also induce cellular injury and that endoplasmic-reticulum-stress is an important mechanism when mutations induce protein misfolding. SUMMARY: Identifying genetic subsceptibility factors for a disease never completely uncovers its underlying pathogenesis or potential treatment targets. This requires studying the mechanisms suggested by genetic findings in experimentel disease models. Pancreatitis is a field, in which much progress has now been achieved by adopting this approach.

Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer.

BACKGROUND/OBJECTIVES: We have recently described copy number variants (CNVs) of the human carboxyl-ester lipase (CEL) gene, including a recombined deletion allele (CEL-HYB) that is a genetic risk factor for chronic pancreatitis. Associations with pancreatic disease have also been reported for the variable number of tandem repeat (VNTR) region located in CEL exon 11. Here, we examined if CEL CNVs and VNTR length polymorphisms affect the risk for developing pancreatic cancer. METHODS: CEL CNVs and VNTR were genotyped in a German family with non-alcoholic chronic pancreatitis and pancreatic cancer, in 265 German and 197 Norwegian patients diagnosed with pancreatic adenocarcinoma, and in 882 controls. CNV screening was performed using PCR assays followed by agarose gel electrophoresis whereas VNTR lengths were determined by DNA fragment analysis. RESULTS: The investigated family was CEL-HYB-positive. However, an association of CEL-HYB or a duplication CEL allele with pancreatic cancer was not seen in our two patient cohorts. The frequency of the 23-repeat VNTR allele was borderline significant in Norwegian cases compared to controls (1.2% vs. 0.3%; P = 0.05). For all other VNTR lengths, no statistically significant difference in frequency was observed. Moreover, no association with pancreatic cancer was detected when CEL VNTR lengths were pooled into groups of short, normal or long alleles. CONCLUSIONS: We could not demonstrate an association between CEL CNVs and pancreatic cancer. An association is also unlikely for CEL VNTR lengths, although analyses in larger materials are necessary to completely exclude an effect of rare VNTR alleles.

Acute Pancreatitis: Genetic Risk and Clinical Implications.

Acute pancreatitis (AP) is one of the most common gastroenterological indications for emergency admittance and hospitalization. Gallstones, alcohol consumption or the presence of additional initiating factors give rise to a disease with a diverse clinical appearance and a hard-to predict course of progression. One major challenge in the treatment of AP patients is the early identification of patients at risk for the development of systemic complications and organ failure. In addition, 20%-30% of patients with a first episode of AP later experience progress to recurrent or chronic disease. Complex gene-environment interactions have been identified to play a role in the pathogenesis of pancreatitis, but so far no predictive genetic biomarkers could be implemented into the routine clinical care of AP patients. The current review explains common and rare etiologies of acute pancreatitis with emphasis on underlying genetic aberrations and ensuing clinical management.

Etiology and Risk Factors of Acute and Chronic Pancreatitis.

Based on the recognition of common etiological and genetic risk factors, acute and chronic pancreatitis are increasingly regarded as a continuum of the same disease, with a significant overlap of clinical manifestations and phenotypes but distinct morphological and imaging appearances. Recent population-based and cohort studies have found that tobacco smoke conveys a greater risk than immoderate alcohol consumption for the development of chronic pancreatitis, and hypertriglyceridemia has been identified as a risk factor for acute pancreatitis - even when plasma levels are only mildly elevated. Hereditary pancreatitis, in its autosomal dominant form, is associated with mutations in the cationic trypsinogen gene (PRSS1), whereas a number of germline variations in other genes have been found to represent risk factors for chronic as well as acute pancreatitis. For now, most of these involve the pancreatic digestive protease/antiprotease system. Oftentimes, affected patients are burdened with multiple or accumulating risk factors, and genetic traits when combined with environmental toxins compound the chance of developing the disease. Determining the underlying etiology of pancreatitis is worth the effort since formerly intractable varieties such as autoimmune pancreatitis are now becoming increasingly treatable, and subtype-specific therapeutic modalities may become available.