The L125F MATE1 variant enriched in populations of Amerindian origin is associated with increased plasma levels of metformin and lactate
Por:
Morales-Rivera, Monserrat I., Alemon-Medina, Radames, Martinez-Hernandez, Angelica, Gomez-Garduno, Josefina, Mirzaeicheshmeh, Elaheh, Altamirano-Bustamante, Nelly F., Ilizaliturri-Flores, Ian, Mendoza-Caamal, Elvia C., Perez-Guille, Maria G., Garcia-Alvarez, Raquel, Contreras-Cubas, Cecilia, Centeno-Cruz, Federico, Revilla-Monsalve, Cristina, Garcia-Ortiz, Humberto, Barajas-Olmos, Francisco, Orozco, Lorena
Publicada:
1 ene 2021
Resumen:
Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug. © 2021 The Authors
Filiaciones:
Morales-Rivera, Monserrat I.:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, CDMX, Mexico
Alemon-Medina, Radames:
Pharmacology Laboratory, Instituto Nacional de Pediatría, SSA, CDMX, Mexico
Martinez-Hernandez, Angelica:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Gomez-Garduno, Josefina:
Pharmacology Laboratory, Instituto Nacional de Pediatría, SSA, CDMX, Mexico
Mirzaeicheshmeh, Elaheh:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Altamirano-Bustamante, Nelly F.:
Endocrinology Department, Instituto Nacional de Pediatría, SSA, CDMX, Mexico
Ilizaliturri-Flores, Ian:
Unidad Profesional Interdisciplinaria de Ingeniería, IPN, Hidalgo, Mexico
Mendoza-Caamal, Elvia C.:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Perez-Guille, Maria G.:
Pharmacology Laboratory, Instituto Nacional de Pediatría, SSA, CDMX, Mexico
Garcia-Alvarez, Raquel:
Pharmacology Laboratory, Instituto Nacional de Pediatría, SSA, CDMX, Mexico
Contreras-Cubas, Cecilia:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Centeno-Cruz, Federico:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Revilla-Monsalve, Cristina:
Medical Research Unit in Metabolic Diseases, UMAE Hospital de Cardiología, Centro Médico Nacional Siglo XXI, IMSS, CDMX, Mexico
Garcia-Ortiz, Humberto:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Barajas-Olmos, Francisco:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
Orozco, Lorena:
Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
gold, Gold
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