Exome Sequence Data of Eight SLC Transporters Reveal That SLC22A1 and SLC22A3 Variants Alter Metformin Pharmacokinetics and Glycemic Control

Abstract

Background: Type 2 diabetes (T2D) is one of the leading causes of mortality and is a public health challenge worldwide. Metformin is the first-choice treatment for T2D; its pharmacokinetics (PK) is facilitated by members of the solute carrier (SLC) superfamily of transporters, it is not metabolized, and it is excreted by the kidney. Although interindividual variability in metformin pharmacokinetics is documented in the Mexican population, its pharmacogenomics is still underexplored. We aimed to identify variants in metformin SLC transporter genes associated with metformin PK and response in Mexican patients. Methods: Using exome data from 2217 Mexican adults, we identified 86 biallelic SNVs in the eight known genes encoding SLC transporters, with a minor allele frequency ≥ 1%, which were analyzed in an inadequate glycemic control (IGC) association study in T2D metformin treated patients. Metformin PK was evaluated in a pediatric cohort and the effect of associated SNVs was correlated. Results: Functional annotation classified two SNVs as pathogenic. The association study revealed two blocks associated with IGC. These haplotypes comprise rs622591, rs4646272, rs4646273, and rs4646276 in SLC22A1; and rs1810126 and rs668871 in SLC22A3. PK profiles revealed that homozygotes of the SLC22A1 haplotype reached lower plasma metformin concentrations 2 h post administration than the other groups. Conclusions: Our findings highlight the potential of pharmacogenomics studies to enhance precision medicine, which may involve dosage adjustments or the exploration of alternative therapeutic options. These hold significant implications for public health, particularly in populations with a high susceptibility to develop metabolic diseases, such as Latin Americans.

Keywords: SLC transporters; SNVs; metformin response; pharmacogenetics; pharmacokinetics; type 2 diabetes.

Figure 1

In silico functional annotation of the 86 SNVs identified in eight metformin transporter genes in the discovery sample, using the Variant Effect Predictor (VEP) software. Each bar shows the VEP consequences classification of the analyzed variants in SLC transporters, the number of genetics variants of each classification is shown within the bar. The red color shows two SNVs classified as pathogenic in SLC22A1 (rs2282143) and SLC47A1 (rs77474263), respectively.

Figure 2

LD analysis for the region harboring the variants in chromosome 6. (a) Diagram of the region located between base pairs 160,551,093 and 160,872,151 on chromosome 6; it includes all SNVs within SLC22A1, SLC22A2, and SLC22A3. (b) LD analysis of SNVs associated with IGC in SLC22A1 (rs4646272, rs4646273, rs4646276, and rs622591). (c) LD analysis of SNVs associated with IGC in SLC22A3 (rs668871 and rs1810126). The grayscale range represents the pair-wise R² between the SNVs, ranging from 0 (white) to 1 (black). Black circles near the SNV name indicate the associated SNVs. (d) IGC haplotype association analysis of blocks on SLC22A1 and SLC22A3, * = p-value adjusted by sex, age, BMI, combined therapy, years of T2D diagnosis, and ancestry.

Figure 3

The 24-h plasma metformin concentration curve according to SLC22A1 rs4646272 and rs622591 SNVs. The ancestral homozygous haplotype carriers (purple line) reached only 45.9% of the metformin C_max observed in their homozygous (green line) counterparts between the second and the third hour of metformin administration.