Shah Shailja C, Reese Tyler S, Daniel Laura L, Zanussi Jacy, Dickson Alyson L, Nepal Puran, Tao Ran, Miller-Fleming Tyne, Straub Peter, Maizel Jennifer, Hung Adriana M, Wei Wei-Qi, Phillips Elizabeth J, Cox Nancy J, Stein C Michael, Feng QiPing, Chung Cecilia P
Division of Gastroenterology, University of California, San Diego, California, USA.
VA San Diego Healthcare System, San Diego, California, USA.
Clin Pharmacol Ther. 2025 Oct;118(4):946-953. doi: 10.1002/cpt.70003. Epub 2025 Jul 23.
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), which was replicated in All of Us (OR = 2.70, P = 4.18E). 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.
硫唑嘌呤用于治疗多种炎症性和自身免疫性疾病。然而，其应用受到严重不良事件的限制，包括急性胰腺炎。先前的研究发现HLA区域与硫嘌呤诱导的急性胰腺炎（TIAP）之间存在关联；然而，在临床实践中，许多胰腺炎患者并不符合这一严格标准。我们旨在通过扩大胰腺炎的定义，利用全基因组和转录组全关联研究（GWAS和TWAS）来确定与硫唑嘌呤相关胰腺炎相关的其他基因。我们对患有炎症性疾病的硫唑嘌呤使用者进行了一项回顾性研究。我们使用了与来自BioVU（范德比尔特生物样本库）的基因组数据相关联的电子健康记录，并使用美国国立卫生研究院的“我们所有人”项目复制了结果。主要结局是急性胰腺炎，次要结局是胰腺损伤。从BioVU纳入了16例胰腺炎患者和2085例对照受试者；“我们所有人”队列纳入了不到20例胰腺炎患者和847例对照受试者。BioVU队列中的GWAS分析（针对遗传血统、性别、年龄和硫唑嘌呤适应症的10个主要成分进行了调整）发现胰腺损伤与RAB19中的rs2948386之间存在关联（优势比=3.47，P=1.46E），这在“我们所有人”项目中得到了复制（优势比=2.70，P=4.18E）。我们还针对上述相同因素进行了TWAS分析，发现基因预测的SERPINB9P1胰腺表达与胰腺损伤之间存在显著关联（BioVU：效应大小=0.42，P=1.48E-5；“我们所有人”项目：效应大小=0.48，P值=0.01）。总之，我们确定了与硫唑嘌呤相关胰腺损伤的两个新的基因关联：SERPINB9P1的预测表达和RAB19中的一个单核苷酸多态性。
