Background: Pancreatitis is a rare, but potentially life-threatening adverse event associated with the use of azathioprine. Prior studies have found an association between the HLA region and thiopurine-induced acute pancreatitis (TIAP); however, TIAP is generally a diagnosis of exclusion—made only after all other possible causes of pancreatitis have been eliminated. More recently, drug-associated pancreatic injury has been viewed as a continuum that occurs concurrent with other risk factors for pancreatic injury.

Objectives: We aimed to identify novel genetic risk factors associated with pancreatic injury in patients taking azathioprine using genome-wide association studies (GWAS).

Methods: This was a retrospective study of patients with inflammatory conditions taking azathioprine. We used electronic health records linked to genomic data from two independent cohorts of White patients—BioVU (Vanderbilt’s biobank) for discovery and NIH’s All of Us for replication. We excluded patients who underwent organ transplant. The primary outcome was pancreatic injury defined by amylase or lipase levels greater than twice the upper limit of normal while taking azathioprine. In total, we analyzed ~7.1 million single-nucleotide polymorphisms. We conducted the analyses using Firth logistic regression adjusting for 10 principal components, sex, age, and two azathioprine indication variables (inflammatory bowel disease and all others). All of Us does not permit reporting of exact numbers <20.

Results: Forty-two patients with pancreatic injury and 2085 control subjects were included from BioVU; the All of Us cohort included <20 patients with pancreatic injury and 847 control subjects. The GWAS analysis in the BioVU cohort identified an association between pancreatic injury and a SNP at the RAB19 locus (rs2948386, OR=3.47, p=1.46 x 10 ^-8 ); the association was replicated in the All of Us cohort (OR=2.70, p=4.18 x 10 ^-3 ).

Conclusion: In summary, we identified rs2948386 at the RAB19 locus as a novel genetic factor for azathioprine-associated pancreatic injury. Previous reports indicate that Rab19 plays a role in autophagy and the severity of pancreatitis in animal models support its potential underlying mechanistic involvement.

REFERENCES: NIL.

Acknowledgements: We gratefully acknowledge All of Us participants for their contributions, without whom this research would not have been possible. We also thank the National Institutes of Health’s All of Us Research Program for making available the participant dataexamined in this study.

Disclosure of Interests: None declared.