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RAB19, SERPINB9P1, and Pancreatitis in Patients Taking Azathioprine in Routine Clinical Practice: Genome and
Shailja C Shah1,2, Tyler S Reese3, Laura L Daniel4
1Division of Gastroenterology, University of California, San Diego, California, USA.
Clinical Pharmacology and Therapeutics
|July 23, 2025
Summary
Azathioprine can cause pancreatitis, a serious side effect. New genetic discoveries in RAB19 and SERPINB9P1 may help predict and prevent this adverse drug reaction in patients.
Area of Science:
- Pharmacogenomics
- Gastroenterology
- Immunology
Background:
- Azathioprine is a crucial medication for autoimmune and inflammatory diseases.
- Serious adverse events, such as acute pancreatitis, limit azathioprine's clinical utility.
- Previous research linked HLA region genes to thiopurine-induced acute pancreatitis, but a broader genetic basis is suspected.
Purpose of the Study:
- To identify novel genetic factors associated with azathioprine-related pancreatitis beyond the established HLA association.
- To broaden the definition of pancreatitis for a more inclusive genetic analysis.
- To leverage genome-wide and transcriptome-wide association studies for discovering new genetic risk markers.
Main Methods:
- Retrospective analysis of azathioprine users with inflammatory conditions using electronic health records and genomic data.
- Utilized BioVU (Vanderbilt's biobank) for initial discovery and NIH's All of Us cohort for replication.
- Employed genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS), adjusting for relevant covariates.
Main Results:
- GWAS identified a significant association between pancreatic injury and a single nucleotide polymorphism (SNP) rs2948386 in the RAB19 gene (OR=3.47, P=1.46E-8) in the BioVU cohort, replicated in All of Us (OR=2.70, P=4.18E-3).
- TWAS revealed a significant association between the genetically predicted pancreatic expression of SERPINB9P1 and pancreatic injury (BioVU: effect size=0.42, P=1.48E-5; All of Us: effect size=0.48, P=0.01).
- These findings implicate RAB19 and SERPINB9P1 in the etiology of azathioprine-induced pancreatic injury.
Conclusions:
- Two novel genetic associations, a RAB19 SNP and predicted SERPINB9P1 expression, are linked to azathioprine-related pancreatic injury.
- These discoveries offer potential biomarkers for identifying patients at higher risk of pancreatitis.
- Further research can explore the functional mechanisms of RAB19 and SERPINB9P1 in azathioprine-induced pancreatic toxicity.
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