Daniel Laura L, Nepal Puran, Zanussi Jacy, Dickson Alyson L, Straub Peter, Miller-Fleming Tyne W, Wei Wei-Qi, Hung Adriana M, Cox Nancy J, Kawai Vivian K, Mosley Jonathan D, Stein Charles Michael, Feng QiPing, Liu Ge, Tao Ran, Chung Cecilia P
Department of Medicine, University of Miami, Coral Gables, Florida, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Clin Transl Sci. 2025 Jun;18(6):e70220. doi: 10.1111/cts.70220.
Leukopenia is a common dose-dependent side effect of azathioprine, often leading to drug discontinuation. Variants in TPMT and NUDT15 are associated with azathioprine-induced leukopenia but only explain 25% of cases. Thus, we aimed to identify novel genetic risk factors among TPMT and NUDT15 normal metabolizers through a genome-wide association study (GWAS). Using BioVU, Vanderbilt's electronic health record linked to genetic data, we assembled a discovery cohort of new users of azathioprine. The analysis was conducted in 1184 new users of azathioprine who had no history of prior thiopurine use or an organ transplant. A replication cohort of 521 patients was derived from All of Us, an NIH-funded project that links healthcare data and genetics. The GWAS was adjusted for sex, age, indication (inflammatory bowel disease, systemic lupus erythematosus, other autoimmune condition, or unknown), concurrent use of xanthine oxidase inhibitors (allopurinol or febuxostat) or immunosuppressants, prior TPMT or NUDT15 testing, and 10 principal components of ancestry. In BioVU, 65% of patients were female with a median age of 44 [IQR: 30, 57] and 125 patients developed leukopenia. In All of Us, 69% were female with a median age of 51 [36, 61], and 44 patients developed leukopenia. An intronic variant in PTPN2, rs11664064, reached genome-wide significance in BioVU (OR = 3.61; p = 1.96E-8) and replicated in All of Us (OR = 2.42, p = 0.039). Our finding suggests an association between rs11664064 in PTPN2 and azathioprine-induced leukopenia. PTPN2 plays a role in immune cell development and differentiation, providing a plausible mechanism for this association.
白细胞减少是硫唑嘌呤常见的剂量依赖性副作用，常导致停药。TPMT和NUDT15基因的变异与硫唑嘌呤引起的白细胞减少有关，但仅能解释25%的病例。因此，我们旨在通过全基因组关联研究（GWAS）在TPMT和NUDT15正常代谢者中识别新的遗传风险因素。利用范德堡大学与遗传数据相关联的电子健康记录BioVU，我们组建了一个硫唑嘌呤新使用者的发现队列。分析在1184名无硫嘌呤使用史或器官移植史的硫唑嘌呤新使用者中进行。一个由521名患者组成的复制队列来自“我们所有人”项目，这是一个由美国国立卫生研究院资助的将医疗保健数据与遗传学相联系的项目。GWAS针对性别、年龄、适应症（炎症性肠病、系统性红斑狼疮、其他自身免疫性疾病或不明）、同时使用黄嘌呤氧化酶抑制剂（别嘌醇或非布司他）或免疫抑制剂、先前的TPMT或NUDT15检测以及10个祖先主成分进行了校正。在BioVU中，65%的患者为女性，中位年龄为44岁[四分位间距：30，57]，125名患者出现白细胞减少。在“我们所有人”项目中，69%为女性，中位年龄为51岁[36，61]，44名患者出现白细胞减少。PTPN2基因的一个内含子变异rs11664064在BioVU中达到全基因组显著性（OR = 3.61；p = 1.96E - 8），并在“我们所有人”项目中得到复制（OR = 2.42，p = 0.039）。我们的发现表明PTPN2基因中的rs11664064与硫唑嘌呤引起的白细胞减少之间存在关联。PTPN2在免疫细胞的发育和分化中起作用，为这种关联提供了一个合理的机制。
