Pharmacogenetic determinants of thiopurines in an Indian cohort.

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 NUDT153, NUDT155, TPMT3C, TPMT3B variant alleles were 6.78%, 0.11%, 1.98% and 0.69%, respectively. TPMT3A 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 NUDT153 and 60% subjects heterozygous for TPMT3C exhibit thiopurine-mediated hematological toxicity. NUDT15 variants have no impact on the binding of 'dGTP' to the NUDT protein. NUDT153 variant increases aggregation 'hot spot' region and induces unfavourable torsion in the protein. NUDT155 destabilizes the protein and impairs Mg/Mn binding. TPMT3A, TPMT3B and TPMT3C variants lower binding affinity to 6-mercaptopurine compared to the wild protein. TPMT3C variant destabilizes the TPMT protein in the thermal experiment. Compared to the data of European and African/African American populations, NUDT153 frequency is higher and TPMT*3C frequency is lower in our population.

CONCLUSIONS

TPMT variants were less frequent in Indian population, while NUDT153 is more frequent compared to European and African/African American populations. NUDT153 increases aggregation 'hot spot' and induces unfavourable torsion in the protein. NUDT155 and TPMT3C destabilize the respective proteins. TPMT3A, TPMT3B and TPMT*3C are associated with a lower binding affinity towards 6-mercaptopurine.