Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Abstract

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Figure 1

Pharmacogenetic impact of rs8192675 on metformin response in participants of European ancestry. The forest plots show meta-analyses of association test results for metformin-induced change in HbA1c in a total of 10,557 participants from 10 MetGen cohorts. Results from linear regression models with (left) and without (right) adjustment for baseline HbA1c are presented. The x axis represents the impact on metformin-induced HbA1c reduction of each copy of the C allele. HbA1c was measured in percentage.

Figure 2

HbA1c reduction by BMI group and rs8192675 genotype. Participants were stratified into obese (BMI ≥ 30 kg/m2) and nonobese (BMI < 30 kg/m2) groups. The number of obese and nonobese individuals in each genotype group is noted along the x axis. Error bars, s.e.m.

Figure 3

Regional plots of the SLC2A2 locus. SNPs are plotted by position on chromosome 3 against association with meta-analysis of HbA1c reduction without baseline adjustment (−log₁₀ P) in 7,223 participants (left) and meta-analysis of SLC2A2 expression (−log₁₀ P) in 1,226 liver samples (right). In both plots rs8192675 (purple circle) and its proxies are the top signals. The nonsynonymous SNP rs5400 (arrow) was also nominally associated with HbA1c reduction. Estimated recombination rates (cM/Mb) are plotted in blue to reflect the local LD structure. The SNPs surrounding the most significant SNP, rs8192675, are color coded to reflect their LD with this SNP. This LD was taken from pairwise r² values from the HapMap CEU data. Genes, the position of exons and the direction of transcription from the UCSC Genome Browser are noted.

Figure 4

Genetic impact of GLUT2 variants on glucose homeostasis in different physiological and pharmacologic states. In patients with the monogenic Fanconi–Bickel syndrome (FBS), the loss-of-function variants led to lower fasting glucose but higher post-prandial glucose; the expression-reducing C allele at rs8192675 was associated with lower HbA1c in normal glycemia state but higher HbA1c in hyperglycemia state (before pharmacological treatment was indicated in patients with type 2 diabetes (T2D)); metformin but not sulfonylurea treatment reversed the genetic impact on HbA1c.