Assessment of thiopurine S-methyltransferase allele frequencies and phenotype–genotype concordance in a Tunisian population

Abstract

Abstract Objectives Thiopurine S-methyltransferase (TPMT) polymorphisms are associated with low or absent enzyme activity and, consequently, increased myelosuppression risk after conventional doses of azathioprine. The distribution of frequencies for deficient TPMT genotypes differs between ethnic groups. Due to limited data in Tunisia, we aimed to detect TPMT variant alleles ( TPMT *2, *3B, *3C, *4) in Tunisian patients on azathioprine, and to investigate the concordance between TPMT phenotyping and genotyping for common TPMT alleles. Methods We conducted a total of 32 genotyping assays in patients treated with azathioprine, who were referred to the Clinical Pharmacology Department for therapeutic monitoring of azathioprine metabolites from 2021 to 2024. TPMT phenotyping was performed by measuring azathioprine metabolites (6-TGN and 6-MMP) in patients’ red blood cells using HPLC method. TPMT genotyping was performed using next generation sequencing to detect the following nucleotide substitutions: c.238G>C, c.460G>A, c.719A>G and c.626-1G>A. Results Twenty-eight patients (87.5 %) were homozygous for the wild type. Four individuals (12.5 %) were TPMT deficient subjects and all carriers for TPMT *3C allele. No individual was carrier of the TPMT *2 or *4 allele. The overall concordance between genotyping and phenotyping in this population was 68.8 %. Conclusions Overall, 12.5 % of the Tunisian subjects were found to carry the TPMT *3C allele. However, detecting novel and rare TPMT alleles within a larger cohort essential for more accurate estimation of genotype–phenotype correlation in our population. Combining genotyping and phenotyping is likely represents the most effective approach to prevent life-threatening myelosuppression associated with thiopurines.