Table5_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似。然而，许多患者遭受了可能与遗传变异部分相关的副作用。本研究旨在识别与诱导阶段使用的药物相关的遗传变异，并分析其对副作用贡献，同时考虑个体的遗传谱系。在200名患者中，对与泼尼松、长春新碱和L-门冬酰胺酶相关的五个基因（ABCB1、CYP3A5、CEP72、ASNS和GRIA1）中的十个多态性进行了基因分型。通过使用45个遗传谱系信息标记（AIMs）确定了谱系。样本的遗传谱系为69.2%欧洲血统、20.1%美洲原住民血统和10.7%非洲血统，但存在高度异质性。口腔炎、库欣综合征和神经毒性是唯一与遗传变异和谱系相关的副作用。口腔炎与ASNS（rs3832526；3R/3R与2R携带者；OR：= 6.88 [1.88–25.14]，p = 0.004）和CYP3A5（非表达者与表达者；OR：4.55 [1.01–20.15]，p = 0.049）基因显著相关。至于库欣综合征，具有TA基因型（rs1049674，ASNS）的患者比具有TT基因型的患者更有可能发生库欣综合征（OR：2.60 [1.23–5.51]，p = 0.012）。神经毒性则与ABCB1（rs9282564；TC与TT；OR：4.25 [1.47–12.29]，p = 0.007）显著相关。此外，患者