Association of TPMT and NUDT15 gene polymorphisms with azathioprine-induced leukopenia: A case–control study in Eastern India

Abstract: BACKGROUND: Azathioprine (AZA) is a widely used immunosuppressant drug. Leukopenia is a serious adverse effect of the drug which often necessitates dose reduction or drug withdrawal. Predictors of leukopenia include genetic and nongenetic factors. Genetic polymorphism of AZA-metabolizing enzyme, thiopurine S-methyltransferase ( TPMT) is well established. There is inconclusive evidence about the role of Nudix hydrolase ( NUDT15) gene polymorphism. This case–control study assessed the association of genetic polymorphisms of NUDT15 and TPMT with leukopenia induced by AZA. MATERIALS AND METHODS: Cases were patients on AZA who developed leukopenia (white blood cell count <4000/μl) within 1 year of treatment initiation that necessitated dose reduction or drug withdrawal. Age and gender-matched patients without leukopenia within 1 year of treatment with AZA served as controls. TPMT (3 loci: c238G to C, c460G to A, c719A to G) and NUDT15 (c 415C to T, rs116855232) genotyping were done using TPMT strip assay and polymerase chain reaction–restriction fragment length polymorphism, respectively. Genotype frequencies were noted, and the odds ratio was calculated to determine the association between genotypes and leukopenia. RESULTS: Twenty-nine subjects (15 cases and 14 controls) were enrolled. Statistically significant differences were not observed in the TPMT genotype (*1/*1 and *1/*3C) ( P = 0.23) between cases and controls. NUDT15 genotypes (*1/*1 and *1/*3) ( P = 0.65) also showed no statistically significant difference between cases and controls. CONCLUSION: The above genotypes do not appear to be associated with AZA-induced leukopenia in an eastern Indian population.