RESUMEN
Purpose: Thiopurine S-methyltransferase (TPMT) is an enzyme that metabolizes purine analogs, agents used in the treatment of acute lymphoblastic leukemia. Improper drug metabolism leads to toxicity in chemotherapy patients and reduces treatment effectiveness. TPMT variants associated with reduced enzymatic activity vary across populations. Therefore, studying these variants in heterogeneous populations, such as Ecuadorians, can help identify molecular causes of deficiency for this enzyme. Methods: We sequenced the entire TPMT coding region in 550 Ecuadorian individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnicities. Moreover, we conducted an ancestry analysis using 46 informative ancestry markers. Results: We identified 8 single nucleotide variants in the coding region of TPMT. The most prevalent alleles were TPMT*3A, TPMT*3B, and TPMT*3C, with frequencies of 0.055, 0.012, and 0.015, respectively. Additionally, we found rare alleles TPMT*4 and TPMT*8 with frequencies of 0.005 and 0.003. Correlating the ancestry proportions with TPMT-deficient genotypes, we observed that the Native American ancestry proportion influenced the distribution of the TPMT*1/TPMT*3A genotype (OR = 5.977, p = 0.002), while the contribution of African ancestral populations was associated with the TPMT*1/TPMT*3C genotype (OR = 9.769, p = 0.003). The rates of TPMT-deficient genotypes observed in Mestizo (f = 0.121) and Indigenous (f = 0.273) groups provide evidence for the influence of Native American ancestry and the prevalence of the TPMT*3A allele. In contrast, although Afro-Ecuadorian groups demonstrate similar deficiency rates (f = 0.160), the genetic factors involved are associated with contributions from African ancestral populations, specifically the prevalent TPMT*3C allele. Conclusion: The distribution of TPMT-deficient variants offers valuable insights into the populations under study, underscoring the necessity for genetic screening strategies to prevent thiopurine toxicity events among Latin American minority groups.
RESUMEN
Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are treated with immunosuppressive purine analogs, 6-mercaptopurine/6-thioguanine/azathiopurine, which are inactivated by thiopurine S-methyltransferase (TPMT). Non-synonymous polymorphisms in TPMT are associated with increased risk of adverse effects in patients treated with thiopurines. This study aimed to determine the frequency of the most common mutant TPMT alleles in Mexican patients with SLE (a prototype autoimmune disease) and RA (one of the most common autoimmune diseases in Mexico). Five hundred fifty-three consecutive patients from Central Mexico with SLE (178) and RA (375) were included. Subjects were genotyped to identify TPMT*2 (rs1800462), TPMT*3A (rs1800460 and rs1142345), TPMT*3B (rs1800460), and TPMT*3C (rs1142345) mutant alleles. DNA samples were assayed with the 5' exonuclease technique and TaqMan probes. Mutant alleles were detected in 6.2 and 5.2% of SLE and RA cases, respectively. Of note, 12.4% of SLE cases and 10.1% of RA cases carried mutant genotypes. Among those, the null genotype (TPMT*2/*3A, 0.3%) and the TPMT*3B (0.5%) and TPMT*3C (1.0%) alleles were found in RA, but not SLE cases. Mexican SLE cases displayed the highest frequency of mutant TPMT genotypes worldwide. TPMT genotyping should be performed for Mexican patients with SLE and RA before prescribing purine analogs.