Pharmacogenetic determinants of thiopurines in an Indian cohort
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ARTICLE
Pharmacogenetic determinants of thiopurines in an Indian cohort Shaik Mohammad Naushad1 · Mekala Janaki Ramaiah2 · Vijay Kumar Kutala3 · Tajamul Hussain4,5 · Salman A. Alrokayan5,6 Received: 4 July 2020 / Revised: 25 August 2020 / Accepted: 4 September 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background 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. Methods 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. Results 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. Conclusions 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.
* Shaik Mohammad Naushad [email protected] 1
Department of Biochemical Genetics and Pharmacogenomics, Sandor Speciality Diagnostics Pvt Ltd, Banjara Hills, Road No 3, Hyderabad 500034, India
2
School of Chemical and Biotechnology, SASTRA University, Thanjavur, India
3
Department of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, India
4
Center of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
5
Biochemistry Department, College of Science, Research Chair for Biomedical Applications of Nanomaterials, King Saud University, Riyadh 11451, Saudi Arabia
6
Biochemistry Department, College of Science, King Saud University, R
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