In Ariel Precision Medicine’s latest research initiative, published in the journal Pancreas, researchers hypothesized that some pancreatitis etiology originates in pancreatic acinar or duct cells and requires both injury and compensatory mechanism failure. To test this hypothesis, researchers analyzed genetic data of 100 patients, who had volunteered to participate, using Ariel’s targeted next-generation sequencing panel, PancreasDx. What was found, is evidence that suggests a new, non-Mendelian genetic risk/etiology paradigm where a combination of nonpathogenic genetic risk variants in groups of susceptibility genes and injury/dysfunction response genes contribute to acquired pancreatic disease.
What we know about the genetics of pancreatitis
Pancreatitis has many causes. In a minority of people, pancreatitis is caused by genetic variants in a single gene. These so-called monogenic forms of pancreatitis are typically passed down in a family. Most genetic testing focuses on these rare forms of pancreatitis, such as hereditary pancreatitis, or the kind caused by the genetic condition cystic fibrosis.
However, most cases of pancreatitis are caused by a combination of several genetic and environmental risk factors, and often there is no family history of the disease. In this study, Ariel researchers took a deeper dive into this second type of pancreatitis.
A model of how genes affect pancreatitis
A simple model of pancreatitis development consists of an imbalance of two opposing forces: stress and protection. When the stresses – like genetic factors and smoking – overwhelm the ways the pancreas protects itself from injury, pancreatitis develops. This can result from an increase in stress, or a decrease in protection. In this study, the researchers tested whether increased stress and decreased protection in the form of genetic variants is related to more severe disease.
To answer this question, the researchers investigated whether some types of genetic variants are more likely to be found together in people with the disease than in others, and whether these variants coincided with increased stress and decreased protection. The genetic variants for the study were identified in 100 people who underwent genetic testing for pancreatitis using Ariel’s PancreasDx® panel and agreed to participate in research. Most of the research participants had recurrent acute pancreatitis (57%) or chronic pancreatitis (41%).
The study examined genetic variants found in 8 genes. Based on the model described earlier, the genes SPINK1, CTRC, GGT1 and UBR1 were classified as protective genetic regions, while CFTR, CEL, CPA1, and PRSS1 were classified as stress, or susceptibility genetic regions.
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IAre there genetic variant patterns in pancreatitis patients?
To see if any variants found in research participants may be related to increased risk of pancreatitis, how often variants were identified in people with pancreatitis was compared with how often these variants were found in the general population. As has long been known, most variants represent harmless interpersonal variation, and so most variants were not found to be associated with disease. However, 15 variants were found to be more common in participants than expected, suggesting that they may be harmful.
Next, researchers looked for relationships between different variants within genes and between genes. They tested how often two variants occurred with each other in a single person with pancreatitis. As expected, some genetic variants were commonly found together in the same gene. This is because multiple genes or chunks of DNA tend to be inherited together. These variants that are near each other or in the same gene that are inherited together form what is called a haplotype. When a haplotype is associated with disease, typically only one variant is harmful. Knowing which variants are present in a disease-associated haplotype helps researchers determine which variant is harmful.
Last, combinations of variants in different genes were investigated. The findings suggested that variants in both protective and stress genes may co-occur more frequently in individuals with pancreatitis than the general population. For example, variants in the protective region GGT1 had co-occurrence with those in the risk region CFTR, as in the model described above. Support for their combined role in contributing to pancreatitis was found by examining what part of the pancreas these genes are active in. Both GGT1 and CFTR were found to be expressed in the duct of the pancreas. Because this was a small exploratory study, none of the co-occurrences reached statistical significance. Nevertheless, the biological plausibility of the findings provide valuable starting points for future larger studies.
How does this help patients?
Scientific research forms the foundation of all successful clinical tests and treatments. To deliver the best possible individualized treatments for pancreatic disease, it’s important to first understand how certain genetic variants that make us unique might work together to increase risk. This study builds on previous basic research and lays some groundwork for further research studies.
The earlier stages of basic research can then be built upon to devise ways of helping patients in clinic. For example, later studies can involve identifying at-risk people earlier in their disease course, creating new diagnostic tools, developing new medications and ultimately, preventing the disease altogether. Ariel is committed to advancing pancreatitis genetics research in every stage of this pipeline to benefit the pancreatitis patient community.
Ellison M, Spagnolo D, Shelton C, Orlova E, LaRusch J, Whitcomb D, Haupt M. Complex genetics in pancreatitis: insights gained from a new candidate locus panel. Pancreas: July 9, 2020 – Volume Publish Ahead of Print – Issue – doi: 10.1097/MPA.0000000000001612 papancr