Analysis of missense SNPs in the SLC47A1 and SLC47A2 genes affecting the pharmacokinetics of metformin: Computational approach

Abstract

Background: Metformin as an anti-hyperglycaemic drug is commonly used for the treatment of type 2 diabetes mellitus (T2DM). The metformin response is variable due to the interindividual variation of pharmacokinetics which is based on strong genetic background. MATE1 and MATE2 proteins are signifcantly implicated in the pharmacokinetics of metformin. Missense SNPs with high risk of pathogenicity are expected to afect response to metformin via pharmacokinetics. Therefore, the aim of the current study is to determine the efects of missense SNPs in the SLC47A1 and SLC47A2 genes. The structural and functional consequences of all known SLC47A1 and SLC47A2 missense SNPs of the human MATE1 and MATE2 proteins were identifed by various bioinformatics methods (SIFT, PhD-SNP, PolyPhen-2, PROVEAN, PMut, MUpro, I-Mutant 3.0, COACH, RaptorX Binding, ConSurf, STRING). Results: The SLC47A1 variants P186T, L116P and the SLC47A2 variants I158N, L112P, V118G exhibited ΔΔG values less than −1 kcal/mol, and these variants are considered to disrupt the structure and function of MATE1 and MATE2 proteins. SLC47A1 R118Q and SLC47A2 Y273C, V118G may signifcantly disturb protein function and transporting activities according to the analysis of ligand-binding regions. Conclusion: It is suggested that high-risk deleterious missense SNPs may mediate the pharmacokinetics of metformin and may be associated with altered tissue distribution, renal clearance and metformin toxicity. We suppose that our results might serve as potential targets for the studies composed of the development of potential diagnostic and therapeutic strategies based on the relationship between mutations and metformin response.