Population-Specific Distribution of TPMT Deficiency Variants and Ancestry Proportions in Ecuadorian Ethnic Groups: Towards Personalized Medicine

Abstract

Jennifer Gallardo-Cóndor,1 Pablo Naranjo,1 Sebastián Atarihuana,1 Dayana Coello,2 Patricia Guevara-Ramírez,3 Rodrigo Flores-Espinoza,4 Germán Burgos,5,6 Andrés López-Cortés,7,8 Alejandro Cabrera-Andrade9,10 1Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Américas, Quito, Ecuador; 2Laboratorios de Investigación, Universidad de Las Américas, Quito, Ecuador; 3Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador; 4Laboratório de Diagnóstico por DNA (LDD), Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; 5One Health Research Group, Facultad de Medicina, Universidad de Las Américas, Quito, Ecuador; 6Grupo de Medicina Xenomica, Instituto de Ciencias Forenses, Universidad de Santiago de Compostela, Satiago de Compostela, Spain; 7Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador; 8Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain; 9Escuela de Enfermería, Facultad de Ciencias de la Salud, Universidad de Las Américas, Quito, Ecuador; 10Grupo de Bio-Quimioinformática, Universidad de Las Américas, Quito, EcuadorCorrespondence: Alejandro Cabrera-Andrade, Grupo de Bio-Quimioinformática, Universidad de las Américas, UDLAPark 2, redondel del ciclista s/n, Quito, 170124, Ecuador, Tel [phone] Ext.:2717, Email [email protected]: 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.Keywords: thiopurine S-methyltransferase, TPMT deficiency, thiopurine toxicity, pharmacogenetics, ancestry estimation, Ecuadorian ethnic groups

Keywords

• thiopurine s-methyltransferase
• tpmt deficiency
• thiopurine toxicity
• pharmacogenetics
• ancestry estimation
• ecuadorian ethnic groups