TY - JOUR
T1 - The L125F MATE1 variant enriched in populations of Amerindian origin is associated with increased plasma levels of metformin and lactate
AU - Morales-Rivera, Monserrat I.
AU - Alemón-Medina, Radamés
AU - Martínez-Hernández, Angélica
AU - Gómez-Garduño, Josefina
AU - Mirzaeicheshmeh, Elaheh
AU - Altamirano-Bustamante, Nelly F.
AU - Ilizaliturri-Flores, Ian
AU - Mendoza-Caamal, Elvia C.
AU - Pérez-Guillé, María G.
AU - García-Álvarez, Raquel
AU - Contreras-Cubas, Cecilia
AU - Centeno-Cruz, Federico
AU - Revilla-Monsalve, Cristina
AU - García-Ortiz, Humberto
AU - Barajas-Olmos, Francisco
AU - Orozco, Lorena
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - Adverse effect
KW - Lactate
KW - MATE1
KW - Metformin
KW - Pharmacogenetics
KW - SLC
UR - http://www.scopus.com/inward/record.url?scp=85112274358&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2021.112009
DO - 10.1016/j.biopha.2021.112009
M3 - Artículo
C2 - 34388523
AN - SCOPUS:85112274358
SN - 0753-3322
VL - 142
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 112009
ER -