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Story of Discovery: Genetic Insights into Pancreatitis

Since the discovery in the 1990s of the first genetic risk factor associated with pancreatitis by an NIDDK grantee, subsequent studies supported by the Institute have identified a number of genetic variants associated with this disease. Pancreatitis is a disease marked by inflammation of the pancreas. A small gland located near the small intestine, the pancreas is responsible for producing enzymes that, mixed with bile from the gallbladder, aid in the digestion of food. In a healthy pancreas, these enzymes are released in an inactive form, to become activated only when they reach the intestine. However, when the pancreas is inflamed, as in pancreatitis, these enzymes become activated while still within the pancreas, where they degrade the very tissue that produced them, causing episodes of pain ranging from mild to severe, as well as nausea and vomiting. Pancreatitis can be acute, with inflammation resolving within a few days, or chronic, involving long-term inflammation and tissue damage. Over time, chronic pancreatitis leads to permanent damage to the pancreas and an increased risk of pancreatic cancer, one of the most devastating of all malignancies. Currently, there are no cures or preventive therapies for pancreatitis. But, investigations into how pancreatitis develops, including genetic variants that can contribute to this disease, have the potential to improve diagnosis, prevention, and treatment.

A variety of factors may contribute to the development of pancreatitis, often interacting in complex ways, including genetics, gallstones, heavy alcohol use, and other causes; unique combinations of factors may occur in different people. NIDDK-sponsored research has led to advances in the discovery of genetic factors associated with hereditary, chronic, acute, and other forms of pancreatitis. For example, the North American Pancreatic Study 2 (NAPS2) is a multi-center clinical study building on past research to uncover additional genetic markers that may help to identify individuals susceptible to pancreatitis and prevent the disease from developing. Genetic testing for mutations in pancreatitis-related genes based on this knowledge has the potential to provide information not only on disease risk, but also causes, severity, and likelihood of progression.

Following are a few highlights of NIDDK-sponsored research advances over the past few decades that have contributed to an explosion of new knowledge regarding the role of genetic factors in pancreatitis.

Trypsin-related Genetic Factors

In 1996, scientists identified the first pancreatitis-related gene mutation in patients with a rare genetic form of the disease called hereditary pancreatitis. This gene coded for the protein cationic trypsinogen, an inactive precursor form of the digestive enzyme trypsin. Trypsinogen is produced by cells in the pancreas then secreted into the small intestine, where it becomes activated to trypsin, an enzyme that breaks down protein and activates other digestive enzymes. Normally, the body has a fail-safe mechanism whereby trypsin is programmed to self-destruct if prematurely activated while still inside the pancreas. However, the mutations in the trypsinogen gene found in patients with hereditary pancreatitis disable this mechanism, enhancing trypsin activation in the pancreas, where it causes cell damage and pancreatitis.

Since that initial groundbreaking discovery, additional mutations associated with pancreatitis were identified in the trypsinogen gene, as well as in other genes that relate to trypsinogen/trypsin function. Mutations in the gene associated with cystic fibrosis—the cystic fibrosis transmembrane conductance regulator gene (CFTR)—were linked in 1998 to the pancreatitis of unknown cause that develops in utero in these patients. CFTR codes for an ion channel that plays an important role in maintaining the fluid that lushes enzymatic precursors like trypsinogen out of the pancreas and into the small intestine. In 2000, mutations in the pancreatic secretory trypsin inhibitory gene (PST1/SPINK1), which encodes a trypsin inhibitory protein, were identified in patients with pancreatitis that cause a loss of this inhibitory function, disabling this first line of defense against prematurely activated trypsin in the pancreas. Later, additional genes coding for proteins that affect trypsin activation, such as the chymotrypsinogen C gene and calcium sensing receptor gene, were also found to contribute to pancreatitis susceptibility.

New Genetic Variants

Recent findings of genetic studies on pancreatitis have pointed to other, non-trypsin-related mechanisms that offer insights into disease development and potential targets for prevention or therapy.

In 2012, the first genome-wide association study of pancreatitis identified a new gene associated with pancreatitis. Using samples collected by the NAPS2 Study from individuals with recurrent acute pancreatitis, chronic pancreatitis, or healthy controls, the researchers scanned their genomes to identify associations with variations in two genetic regions— one in the trypsinogen gene and another in a gene called claudin-2. Claudin-2 is a tight junction protein that regulates the movement of ions and water. The claudin-2 gene variant was strongly associated with chronic pancreatitis, particularly in disease resulting from alcohol abuse in men. This finding could explain, in part, why most patients with alcohol-related pancreatitis are men.

Recently, researchers again used samples from the NAPS2 Study to identify mutations in a gamma-glutamyltransferase 1 (GGT1) gene associated with chronic pancreatitis; these same mutations had been previously linked to pancreatic cancer. The protein formed from this gene typically maintains glutathione levels, which protect cells against damage by free radicals and oxidation. This discovery suggests another mechanism through which pancreatitis may occur—one which may lead not only to inflammation, but also to cancer formation in the pancreas.

Future Directions in Pancreatitis Research

The Institute continues to identify areas of new research opportunity related to pancreatitis, such as genetic risk factors, with help from stakeholders in the external research, professional, and patient advocacy communities.

In June 2012, the Institute convened a two-day research workshop at the NIH campus in Bethesda, Maryland, entitled “Advances in Acute and Chronic Pancreatitis: From Development to Inflammation and Repair.” This workshop provided an update on a wide range of research efforts addressing acute and chronic pancreatitis, including susceptibility genes, and charted a course for advancing future research in this area by addressing current gaps and opportunities. Organizers included NIDDK staff, members of the NIDDK National Advisory Council who are active in this area, and the National Pancreas Foundation, as well as others in the external pancreatitis research community. Presenters from around the globe shared their findings, representing research institutions from the United States, England, Canada, Germany, and Spain. Participants also shared research resources, such as the “Pancreapedia” website, which is supported in part by the NIDDK (www.pancreapedia.org). The proceedings of this workshop continue to guide investigators toward promising future research directions in this area. Consistent with one of its objectives, a report summarizing the meeting was published in the January 2013 issue of the journal Gastroenterology, in order to share knowledge and recommendations with the larger research community focused on advancing understanding and improving care for those with acute and chronic pancreatitis. NIDDK staff also published an article summarizing gaps and opportunities in pancreatic disease research identified in this workshop in the May 2013 issue of the journal Pancreas, to reach a broader portion of the research community and encourage their applications for available funding mechanisms to boost research in this area. In June 2013, the NIDDK and National Cancer Institute co-sponsored a two-day workshop at the NIH campus on “Pancreatitis, Diabetes, Pancreatic Cancer.” The purpose of the workshop was to examine risk factors contributing to the development of pancreatic cancer, to address clinically relevant questions regarding treatment and surveillance of at-risk populations, and to identify opportunities and priorities for further research. Through ongoing NIDDK studies of pancreatitis, such as NAPS2 and the Study of Nutrition in Acute Pancreatitis, as well as new efforts with its research partners, the story of genetic factors in pancreatitis is still being written. And, with this research, chances are steadily increasing for a happy ending where those at risk from pancreatitis are identified and the disease is effectively managed.