A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin

ObjectiveThe aim of this study was to determine the association between the renal clearance (CLrenal) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene-gene interactions between this SNP and (a) the promoter SNP g.-66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes.MethodsFifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied.ResultsWhen analyzed alone, the c.808 (G>T) affected neither the CLrenal nor the secretory clearance (CLsec) of metformin. However, both CLrenal and CLsec were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g.-66T>C: CLrenal: GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P=0.004), respectively and CLsec: GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P=0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g.-66T>C, both CLrenal and CLsec were found to be reduced (P<0.028) when compared with volunteers with minor alleles in c.808 (G>T) carrying the g.-66T>C reference genotype.ConclusionWe report counteracting effects of the c.808 (G>T) and g.-66T>C on the renal elimination of metformin. When adjusted for the genetic variation g.-66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.