Genetic Variants Involved in Metformin Pharmacokinetics in the Chilean Population

To estimate the frequency and potential impact of genetic variants involved in metformin pharmacokinetics, including gastrointestinal absorption, renal elimination, and hepatic transport in the Chilean population.

The frequency of metformin-related gene variants was estimated using data from a genome-wide, exome-focused genotyping array in 918 participants of the Chilean Growth and Obesity Cohort Study (GOCS). Allele frequencies in Chileans were compared with those published worldwide, and the degree of Amerindian/European ancestry was assessed. A predictive bioinformatic analysis was performed on relevant genetic variants using PolyPhen-2.

The genetic polymorphism (p.Leu125Phe; p.L125F; rs77474263; C>T) in the SLC47A1 gene (MATE1 transporter) showed a much higher frequency of the 125Phe (T-allele) in the Chilean population (15.3%) than in non-American populations, being virtually absent in Africa, Europe, or Asia. The 125Phe variant was associated with a higher percentage of Amerindian ancestry in the Chilean population. This result is consistent with a previous report indicating that this variant is enriched in Native American populations, given its high frequency among Mestizo and Indigenous populations in Mexico. The functional variant p.125Phe has been previously suggested to promote plasma metformin accumulation, mitochondrial dysfunction, and increased plasma lactate concentrations by altering renal metformin elimination.

The missense variant p.Leu125Phe (rs77474263) in SLC47A1 is frequent in Chile and Mexico, and apparently absent in non-American populations. In homozygosis, the p.125Phe variant has been previously associated with impaired renal drug elimination, metformin systemic accumulation, and hyperlactatemia.