Table6_Pharmacogenetics of pediatric acute lymphoblastic leukemia in Uruguay: adverse events related to induction phase drugs.DOCX

In Uruguay, the pediatric acute lymphoblastic leukemia (ALL) cure rate is 82.2%, similar to those reported in developed countries. However, many patients suffer adverse effects that could be attributed, in part, to genetic variability. This study aims to identify genetic variants related to drugs administered during the induction phase and analyze their contribution to adverse effects, considering individual genetic ancestry. Ten polymorphisms in five genes (ABCB1, CYP3A5, CEP72, ASNS, and GRIA1) related to prednisone, vincristine, and L-asparaginase were genotyped in 200 patients. Ancestry was determined using 45 ancestry informative markers (AIMs). The sample ancestry was 69.2% European, 20.1% Native American, and 10.7% African, but with high heterogeneity. Mucositis, Cushing syndrome, and neurotoxicity were the only adverse effects linked with genetic variants and ancestry. Mucositis was significantly associated with ASNS (rs3832526; 3R/3R vs. 2R carriers; OR: = 6.88 [1.88–25.14], p = 0.004) and CYP3A5 (non-expressors vs. expressors; OR: 4.55 [1.01–20.15], p = 0.049) genes. Regarding Cushing syndrome, patients with the TA genotype (rs1049674, ASNS) had a higher risk of developing Cushing syndrome than those with the TT genotype (OR: 2.60 [1.23–5.51], p = 0.012). Neurotoxicity was significantly associated with ABCB1 (rs9282564; TC vs. TT; OR: 4.25 [1.47–12.29], p = 0.007). Moreover, patients with

在乌拉圭，儿童急性淋巴细胞白血病（ALL）的治愈率为82.2%，与发达国家报道的治愈率相当。然而，许多患者遭受的不良反应部分可归因于遗传变异。本研究旨在识别与诱导阶段使用的药物相关的遗传变异，并分析其对不良反应的贡献，同时考虑个体的遗传血统。对200名患者的五个基因（ABCB1、CYP3A5、CEP72、ASNS和GRIA1）中的十个多态性进行了基因分型，这些基因与泼尼松、长春新碱和L-门冬酰胺酶相关。血统是通过使用45个血统信息标记（AIMs）确定的。样本血统为69.2%欧洲人、20.1%美洲原住民和10.7%非洲人，但具有高度异质性。口腔炎、库欣综合征和神经毒性是唯一与遗传变异和血统相关的不良反应。口腔炎与ASNS基因（rs3832526；3R/3R对2R携带者；OR：= 6.88 [1.88–25.14]，p = 0.004）和CYP3A5基因（非表达者对表达者；OR：4.55 [1.01–20.15]，p = 0.049）显著相关。至于库欣综合征，具有TA基因型（rs1049674，ASNS）的患者的库欣综合征发病风险高于TT基因型患者（OR：2.60 [1.23–5.51]，p = 0.012）。神经毒性则与ABCB1基因（rs9282564；TC对TT；OR：4.25 [1.47–12.29]，p = 0.007）显著相关。此外，患者