Genetic studies of diseases

Abstract

Pancreatitis is usually inflammation of the pancreas without infection. Our understanding of pancreatitis has been built on autopsy studies, surgical biopsies and surrogate markers of inflammation and fibroses, including abdominal imaging techniques and pancreatic functional studies. However, the discovery that a number of different environmental factors and various genetic abnormalities are seen in patients with similar appearing pancreatitis phenotypes teaches us that end-stage pathology is not the disorder. Understanding complex associations and interactions requires that the components and their interactions be organized, stratified and functionally defined. Systems biology, in the broad sense, provides the approach and tools to define the complex mechanisms driving pathology. As the mathematics behind these pathways and mechanisms are defined and calibrated, the potential pathology of patients with early signs of disease can be predicted, and a number of patient-specific targets for intervention can be defined.

Genetic Risk Factors for Pancreatic Disorders

“…13, 14 . The first hit, AP, activates the immune system and starts the process 14, 15 . Susceptibility to pancreatic injury is linked to premature activation of trypsin—either in acinar cells or pancreatic ducts.…”

“…So the first hit comes from factors that cause injury, whereas the second hit involves factors that promote inflammation and inflammation-associated complications, such as fibrosis and sclerosis, failed acinar cell regeneration, distorted tissue architecture, progressive loss of the normal parenchyma, metaplasia, dysplasia, and pain syndromes. This second hit could include various responses of the immune and autonomic and sensory nervous systems, acinar and duct cell stress responses, cell regeneration and trans-differentiation, tissue remodeling, dysplasia, altered anatomy, and other factors 15 (Figure 1). Different genetic variants can affect each of these systems.…”

Genetic Risk for Alcoholic Chronic Pancreatitis

“…After all pancreatic disease is a complex disorder resulting from multiple defects, which, when combined, lead to failure of control systems and metabolic homeostasis. The determination of the factors, genes, proteins, and cells involved; the pathways that govern its interactions; and where the defects are will provide a better understanding of the pathogenesis of the disease [10]. More than one theory attempts to explain the mechanisms responsible for the development of pancreatitis of alcoholic etiology [11].…”

“…Moreover, there are protection mechanisms directed against pancreatic activation of trypsinogen and prevention of sustained activity of trypsin [10]. The SPINK1 (serine protease inhibitor Kazal type 1) gene encodes a protein inhibitor of trypsin, which is synthesized in acinar cells and is able to inhibit 20% of intracellular activity of trypsin.…”

“…The protection of ductal cells depends on maintaining an alkaline pH and a rapid enzyme flow into the duodenum, which requires normal functioning of CFTR (cystic fibrosis transmembrane conductance regulator or transmembrane conductance regulator Cystic Fibrosis) [10]. This protein is present on the surface of the majority of human epithelial cells and functions as a chloride channel also responsible for the secretion of bicarbonate to pancreatic juices.…”