Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT
Abstract 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 a...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-88963-5 |
| _version_ | 1819195754374234112 |
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| author | Hyery Kim Seungwon You Yoomi Park Jung Yoon Choi Youngeun Ma Kyung Tak Hong Kyung-Nam Koh Sunmin Yun Kye Hwa Lee Hee Young Shin Suehyun Lee Keon Hee Yoo Ho Joon Im Hyoung Jin Kang Ju Han Kim |
| author_facet | Hyery Kim Seungwon You Yoomi Park Jung Yoon Choi Youngeun Ma Kyung Tak Hong Kyung-Nam Koh Sunmin Yun Kye Hwa Lee Hee Young Shin Suehyun Lee Keon Hee Yoo Ho Joon Im Hyoung Jin Kang Ju Han Kim |
| author_sort | Hyery Kim |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-23T02:17:47Z |
| format | Article |
| id | doaj.art-9bbd2fc6cddb40bc9849ee82af01911b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-23T02:17:47Z |
| publishDate | 2021-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9bbd2fc6cddb40bc9849ee82af01911b2022-12-21T18:03:38ZengNature PortfolioScientific Reports2045-23222021-05-0111111310.1038/s41598-021-88963-5Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMTHyery Kim0Seungwon You1Yoomi Park2Jung Yoon Choi3Youngeun Ma4Kyung Tak Hong5Kyung-Nam Koh6Sunmin Yun7Kye Hwa Lee8Hee Young Shin9Suehyun Lee10Keon Hee Yoo11Ho Joon Im12Hyoung Jin Kang13Ju Han Kim14Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of MedicineSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of MedicineSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of MedicineDepartment of Pediatrics, Seoul National University College of MedicineDepartment of Pediatrics, Seoul National University Bundang HospitalDepartment of Pediatrics, Seoul National University College of MedicineDepartment of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of MedicineSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of MedicineSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of MedicineDepartment of Pediatrics, Seoul National University College of MedicineSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of MedicineDepartment of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of MedicineDepartment of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of MedicineDepartment of Pediatrics, Seoul National University College of MedicineSeoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of MedicineAbstract 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.https://doi.org/10.1038/s41598-021-88963-5 |
| spellingShingle | Hyery Kim Seungwon You Yoomi Park Jung Yoon Choi Youngeun Ma Kyung Tak Hong Kyung-Nam Koh Sunmin Yun Kye Hwa Lee Hee Young Shin Suehyun Lee Keon Hee Yoo Ho Joon Im Hyoung Jin Kang Ju Han Kim Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT Scientific Reports |
| title | Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT |
| title_full | Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT |
| title_fullStr | Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT |
| title_full_unstemmed | Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT |
| title_short | Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT |
| title_sort | interplay between il6 and crim1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild type nudt15 and tpmt |
| url | https://doi.org/10.1038/s41598-021-88963-5 |
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