RAB19, SERPINB9P1, and Pancreatitis in Patients Taking Azathioprine in Routine Clinical Practice: Genome and Transcriptome-Wide Association Studies

Azathioprine is used to treat several inflammatory and autoimmune diseases. However, its use is limited by serious adverse events, including acute pancreatitis. Prior studies have found an association between the HLA region and thiopurine-induced acute pancreatitis (TIAP); however, in clinical practice, many patients with pancreatitis do not meet this strict criterion. We aimed to identify additional genes associated with azathioprine-related pancreatitis using genome-wide and transcriptome-wide association studies (GWAS and TWAS) by broadening the definition of pancreatitis. We conducted a retrospective study of azathioprine users with inflammatory conditions. We used electronic health records linked to genomic data from BioVU (Vanderbilt's biobank) and replicated the results using NIH's All of Us. The primary outcome was acute pancreatitis, and the secondary outcome was pancreatic injury. Sixteen patients with pancreatitis and 2085 control subjects were included from BioVU; the All of Us cohort included < 20 patients with pancreatitis and 847 control subjects. The GWAS analysis (adjusted for 10 principal components of genetic ancestry, sex, age, and azathioprine indication) in the BioVU cohort found an association between pancreatic injury and rs2948386 in RAB19 (OR = 3.47, P = 1.46E⁻⁸), which was replicated in All of Us (OR = 2.70, P = 4.18E⁻³). We also conducted a TWAS adjusting for the same factors above and found a significant association between genetically predicted pancreatic expression of SERPINB9P1 with pancreatic injury (BioVU: effect size = 0.42, P = 1.48E-5; All of Us: effect size = 0.48, P-value = 0.01). In summary, we identified two new genetic associations for azathioprine-related pancreatic injury: the predicted expression of SERPINB9P1 and a SNP in RAB19.