Pharmacogenetic determinants of thiopurines in an Indian cohort
| Autor: | Vijay Kumar Kutala, Salman A. H. Alrokayan, Mekala Janaki Ramaiah, Tajamul Hussain, Shaik Mohammad Naushad |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Antimetabolites Antineoplastic Genotype Population Black People India Biology White People Cohort Studies 03 medical and health sciences 0302 clinical medicine Asian People Gene Frequency Humans Pyrophosphatases education Pharmacology African american Genetics education.field_of_study Molecular Structure Thiopurine methyltransferase Mercaptopurine Incidence Computational Biology Leukopenia Methyltransferases General Medicine Variant allele Minor allele frequency Pharmacogenetics 030220 oncology & carcinogenesis Cohort biology.protein Female Metabolic Networks and Pathways 030217 neurology & neurosurgery |
| Zdroj: | Pharmacological Reports. 73:278-287 |
| ISSN: | 2299-5684 1734-1140 |
| DOI: | 10.1007/s43440-020-00158-3 |
| Popis: | Several genetic variants of thiopurine metabolic pathway are associated with 6-thiopurine-mediated leucopenia. A population-based evaluation of these variants lays the foundation for Pharmacogenetic-guided thiopurine therapy. A total of 2000 subjects were screened for the pharmacogenetic determinants using the infinium global screening array (GSA). The functional relevance of these variants was deduced using SNAP2, SIFT, Provean, Mutalyzer, Mutation Taster, Phyre2, SwissDock, AGGRESCAN, and CUPSAT. The minor allele frequencies of NUDT15*3, NUDT15*5, TPMT*3C, TPMT*3B variant alleles were 6.78%, 0.11%, 1.98% and 0.69%, respectively. TPMT*3A genotype was observed in 0.35% subjects. No gender-based differences were observed in the incidence of these variants. Data from studies of the Indian population showed that 92.86% subjects heterozygous for NUDT15*3 and 60% subjects heterozygous for TPMT*3C exhibit thiopurine-mediated hematological toxicity. NUDT15 variants have no impact on the binding of ‘dGTP’ to the NUDT protein. NUDT15*3 variant increases aggregation ‘hot spot’ region and induces unfavourable torsion in the protein. NUDT15*5 destabilizes the protein and impairs Mg/Mn binding. TPMT*3A, TPMT*3B and TPMT*3C variants lower binding affinity to 6-mercaptopurine compared to the wild protein. TPMT*3C variant destabilizes the TPMT protein in the thermal experiment. Compared to the data of European and African/African American populations, NUDT15*3 frequency is higher and TPMT*3C frequency is lower in our population. TPMT variants were less frequent in Indian population, while NUDT15*3 is more frequent compared to European and African/African American populations. NUDT15*3 increases aggregation ‘hot spot’ and induces unfavourable torsion in the protein. NUDT15*5 and TPMT*3C destabilize the respective proteins. TPMT*3A, TPMT*3B and TPMT*3C are associated with a lower binding affinity towards 6-mercaptopurine. |
| Databáze: | OpenAIRE |
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