Association of SLC22A1 gene variants with metformin response in patients with Type 2 diabetes mellitus

INTRODUCTION: ype 2 diabetes mellitus (T2DM) is a common chronic metabolic disorder characterized by impaired insulin secretion and insulin resistance. Metformin is the first-line pharmacological treatment for T2DM; however, substan-tial interindividual variability exists in therapeutic response. Organic cation transporters encoded by the SLC22A1 and SLC22A2 genes play a critical role in metformin transport and pharmacokinetics, and genetic polymorphisms within these genes may contribute to differences in glycemic control. The present study aimed to evaluate the association between SLC22A1 and SLC22A2 gene variants and metformin response in Turkish patients with T2DM.
METHODS: A total of 60 patients with T2DM receiving metformin therapy were included in the study and classified into adequate and inadequate glycemic control groups according to HbA1c levels (<7.0% and >7.0%). Targeted next-gener-ation sequencing analysis of the SLC22A1 and SLC22A2 genes was performed. Identified variants were evaluated under different genetic models, and genotype/allele distributions between groups were compared using Fisher’s exact test.
RESULTS: A total of 20 variants were identified in the SLC22A1 and SLC22A2 genes, including missense, intronic, synon-ymous, and one novel in-frame deletion variant. Most variants were classified as benign, whereas three variants were categorized as variants of uncertain significance. The rs683369: G>C polymorphism showed significant associations with glycemic control under the genotypic, recessive, and allelic models. The CC genotype was observed exclusively in the inadequate glycemic control group under both the genotypic (p=0.041) and recessive models (p=0.042). In ad-dition, the C allele was significantly associated with inadequate glycemic control in the allelic model (p=0.006). Addi-tionally, the novel c.1276+9_1276+16del variant demonstrated a significant allelic association with glycemic control (p=0.049). No significant associations were identified for the rs1867351: T>C or rs628031: A>G variants.
DISCUSSION AND CONCLUSION: Our findings suggest that specific SLC22A1 polymorphisms, particularly rs683369: G>C and the novel c.1276+9_1276+16del variant, may influence the glycemic response to metformin in Turkish patients with T2DM.

Keywords: Diabetes mellitus, gene sequencing, metformin, pharmacogenetic, SLC22A1, SLC22A2