Evaluation of the rs3088442 G>A SLC22A3 Gene Polymorphism and the Role of microRNA 147 in Groups of Adult Pakistani Populations With Type 2 Diabetes in Response to Metformin.

OBJECTIVES: Type 2 diabetes is a complex genetic disorder, and a large number of genetic polymorphisms may be involved in its pathogenesis. Pharmacologically, type 2 diabetes can be treated with 9 different approved classes of drugs, but metformin is suggested as the first line of therapy, followed by sulfonylureas.

METHODS: This was a case-control study consisting of 300 metformin responders and 300 metformin nonresponders in patients with type 2 diabetes and 300 healthy Pakistani subjects. Genotyping of the SLC22A3 G>A polymorphism was performed by allele-specific polymerase chain reaction (PCR) for microRNA 147 expression; real-time polymerase chain reaction was used, and expressional analysis of SLC22A3 was done by semiquantitative polymerase chain reaction.

RESULTS: GA and AA genotypes were highly significantly associated with the drug treatments when compared with controls. A statistically significant difference was observed in the distribution of the SLC22A3 A allele between healthy subjects and patients with type 2 diabetes. When odds ratios were adjusted for glycated hemoglobin levels and postprandial and fasting blood glucose levels, our findings showed that the overexpression of allele A of the rs3088442 G>A variant may act as a protective allele and is associated with the clinical response to metformin. microRNA 147 expression was found to be increased in patients who were metformin responders compared with the nonresponder group and controls. mRNA expression of SLC22A3 was significantly reduced in patients taking metformin as compared to other groups.

CONCLUSIONS: These results suggested that the SLC22A3 rs3088442 at position 2282 A allele may confer metformin clinical responses in patients with type 2 diabetes in the Pakistani population. Overexpression of microRNA 147 is associated with a downward expression of the SLC22A3 gene in patients who have type 2 diabetes.