title: Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response.
abstract: OBJECTIVE
  Metformin is transported into the hepatocyte by organic cation transporter 1 (OCT1) and out of the hepatocyte by multidrug and toxin extrusion 1 (MATE1). Recently, we discovered that polymorphisms rs622342 A>C in the SLC22A1 gene, coding for OCT1, and rs2289669 G>A in the SLC47A1 gene, coding for MATE1, are associated with the degree of glucose lowering by metformin. In this study, we assessed whether there exists an interaction between these two polymorphisms.
  
  
  METHODS
  We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Multiplicative interaction between the polymorphisms and change in HbA1c levels was analyzed in 98 incident metformin users.
  
  
  RESULTS
  In incident metformin users with the OCT1 rs622342 AA genotype, genetic variation at the MATE1 rs2289669 polymorphism was not associated with change in HbA1c levels [-0.10; 95% confidence interval (CI): -0.35 to 0.14; P=0.39]. In users with the OCT1 rs622342 AC genotype, there was a tendency between rs2289669 polymorphisms and change in HbA1c (-0.31; 95% CI: -0.65 to 0.03; P=0.070) and in users with the OCT1 rs622342 CC genotype there was a significant association with change in HbA1c levels (-0.68; 95% CI: -1.06 to -0.30; P=0.005). The multiplicative interaction between these two genotypes was statistically significant (-0.52; 95% CI: -0.94 to -0.11; P=0.015).
  
  
  CONCLUSIONS
  The effect of the MATE1 rs2289669 polymorphism on the glucose lowering effect of metformin is larger in incident users with the OCT1 rs622342 CC genotype than in incident users with the AA genotype. The effect in incident users with the OCT1 rs622342 AC genotype is in between.
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Matthijs L
authors.initials: ML
authors.lastname: Becker
authors.forename: Loes E
authors.initials: LE
authors.lastname: Visser
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Bruno H Ch
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D000368:Aged; D000483:Alleles; D005260:Female; D005838:Genotype; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000378:metabolism / Q000494:pharmacology*; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; C494165:POU2F1 protein, human; C521869:SLC47A1 protein, human