Yang Jing, Wang Peile, Qin Zifei, Jia Mengmeng, Zhang Congmin, Tian Xueke, Zheng Yunbo, Zhang Ailing, Zhang Xiaojian, Liu Shengyun
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Rheumatology and Immunology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Genet Test Mol Biomarkers. 2019 Oct;23(10):751-757. doi: 10.1089/gtmb.2018.0313. Epub 2019 Sep 26.
Azathioprine (AZA) is commonly used to treat autoimmune diseases, but its applications have been limited due to significant adverse effects, particularly leukopenia. The aim of this study was to investigate the associations of , , and inosine triphosphatase () polymorphisms with AZA-induced toxicity. A total of 86 Chinese patients with autoimmune diseases were recruited, and the *2-*6, 3C, and genotypes of these patients were characterized by Sanger sequencing. Sociodemographic data and clinical records over a period of 6 months were also collected. The 3C and 3 genotypes were significantly associated with AZA-induced leukopenia ( = 0.007 and 4.475 × 10, respectively). The -value for the correlation between and leukopenia was 0.059. In addition, 3 was significantly associated with gastrointestinal effects, erythropenia, hypochromia, and thrombocytopenia [ = 0.002, 1.109 × 10, 1.653 × 10, and 9.110 × 10, respectively; allelic odds ratio (95% confidence interval): 5.714 (1.56-20.95), 9.333 (2.96-29.47), 13.18 (4.15-41.87), and 20.13 (3.40-119.18), respectively]. The genotypes were also significantly associated with gastrointestinal discomfort [ = 0.028, 12.08 (0.71-204.49)], alopecia [ = 2.864 × 10, 33 (1.80-606.47)], and hypochromia [ = 0.045, 10.33 (0.61-173.66)]. This study demonstrated that and are both highly predictive genetic markers for AZA-induced toxicity in Chinese populations with rheumatic diseases.
硫唑嘌呤（AZA）常用于治疗自身免疫性疾病，但其应用因显著的不良反应，尤其是白细胞减少症而受到限制。本研究的目的是调查肌苷三磷酸酶（ITPA）基因多态性与AZA诱导的毒性之间的关联。共招募了86例中国自身免疫性疾病患者，通过桑格测序对这些患者的ITPA 2-6、3C和ITPA基因型进行了鉴定。还收集了6个月期间的社会人口统计学数据和临床记录。3C和3基因型与AZA诱导的白细胞减少症显著相关（分别为P = 0.007和4.475×10）。ITPA与白细胞减少症之间相关性的P值为0.059。此外，3与胃肠道效应、红细胞减少症、低色素血症和血小板减少症显著相关[分别为P = 0.002、1.109×10、1.653×10和9.110×10；等位基因优势比（95%置信区间）：分别为5.714（1.56 - 20.95）、9.333（2.96 - 29.47）、13.18（4.15 - 41.87）和20.13（3.40 - 119.18）]。ITPA基因型也与胃肠道不适[P = 0.028，12.08（0.71 - 204.49）]、脱发[P = 2.864×10，33（1.80 - 606.47）]和低色素血症[P = 0.045，10.33（0.61 - 173.66）]显著相关。本研究表明，ITPA和ITPA在中国风湿性疾病人群中都是AZA诱导毒性的高度预测性遗传标记。
