Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.
Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
Sci Rep. 2021 May 6;11(1):9676. doi: 10.1038/s41598-021-88963-5.
NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite the impact of homozygous CRIM1 on thiopurine toxicity, several patients with wild-type NUDT15, TPMT, and CRIM1 experience thiopurine toxicity, therapeutic failure, and relapse of acute lymphoblastic leukemia (ALL). Novel pharmacogenetic interactions associated with thiopurine intolerance from hematological toxicities were investigated using whole-exome sequencing for last-cycle 6-mercaptopurine dose intensity percentages (DIP) tolerated by pediatric ALL patients (N = 320). IL6 rs13306435 carriers (N = 19) exhibited significantly lower DIP (48.0 ± 27.3%) than non-carriers (N = 209, 69.9 ± 29.0%; p = 0.0016 and 0.0028 by t test and multiple linear regression, respectively). Among 19 carriers, 7 with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7 ± 8.9%) than those with IL6 (N = 12, 61.6 ± 25.1%) or CRIM1 (N = 94, 68.1 ± 28.4%) variants. IL6 and CRIM1 variants showed marked inter-ethnic variability. Four-gene-interplay models revealed the best odds ratio (8.06) and potential population impact [relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67), and number needed to genotype (12.50)]. Interplay between IL6 rs13306435 and CRIM1 rs3821169 was suggested as an independent and/or additive genetic determinant of thiopurine intolerance beyond NUDT15 and TPMT in pediatric ALL.
NUDT15 和 TPMT 变体是导致巯嘌呤诱导的血液毒性的强烈遗传决定因素。尽管纯合 CRIM1 对巯嘌呤毒性有影响，但许多具有野生型 NUDT15、TPMT 和 CRIM1 的患者仍会出现巯嘌呤毒性、治疗失败和急性淋巴细胞白血病 (ALL) 复发。使用全外显子组测序研究了与血液毒性相关的新型药物遗传学相互作用，以确定儿科 ALL 患者最后一周期 6-巯基嘌呤剂量强度百分比 (DIP) 可耐受的患者 (N = 320)。IL6 rs13306435 携带者 (N = 19) 的 DIP 明显低于非携带者 (N = 209，69.9 ± 29.0%；p = 0.0016 和 0.0028，分别为 t 检验和多元线性回归)。在 19 名携带者中，7 名同时携带杂合 IL6 rs13306435 和 CRIM1 rs3821169 的患者的 DIP 明显低于 IL6 携带者 (N = 12，61.6 ± 25.1%) 或 CRIM1 携带者 (N = 94，68.1 ± 28.4%)。IL6 和 CRIM1 变体在不同种族之间表现出明显的变异性。四基因相互作用模型显示出最佳的优势比 (8.06) 和潜在的人群影响 [相对风险 (5.73)、人群归因分数 (58%)、需要治疗的人数 (3.67) 和需要基因分型的人数 (12.50)]。IL6 rs13306435 和 CRIM1 rs3821169 之间的相互作用被认为是儿科 ALL 中除 NUDT15 和 TPMT 之外的独立和/或附加遗传决定因素。
