Prevalence of TPMT and NUDT15 pharmacogenomic variants in a diverse germline testing cohort from India

Introduction Thiopurines are cytotoxic antimetabolites used in malignancies and autoimmune conditions, with their clinical use requiring careful monitoring due to the risk of severe myelosuppression driven by the accumulation of active thioguanine nucleotides. This toxicity is largely driven by impaired metabolism of thiopurine metabolites, particularly in individuals with TPMT or NUDT15 variants. The prevalence and spectrum of these pharmacogenomic variants in the Indian population remain incompletely characterized.Materials and methods We analyzed whole-exome data from 1,742 Indian individuals (including 609 with hematologic conditions) to assess clinically relevant pharmacogenomic variants per CPIC guidelines, identifying TPMT *3C and *3B no-function alleles in 3.10% (n = 54).Results The high-risk NUDT15 c.415C >T (*2/*3) variant was identified at an allele frequency of 7.26% (245 carriers; 14.06% of the cohort), including eight homozygotes. Comparative analyses demonstrated pronounced population-specific variation, with several alleles enriched in South Asians but rare or absent in other populations.Conclusion To our knowledge, this represents the largest pharmacogenomic assessment of TPMT and NUDT15 variants in an Indian cohort to date. These findings underscore the importance of incorporating population-specific genomic data into clinical decision-making frameworks and support the implementation of preemptive TPMT and NUDT15 genotyping prior to initiation of thiopurine therapy in Indian patients.