Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients.
OBJECTIVE
Metformin is the most widely used oral antidiabetic drug for the treatment of type 2 diabetes (T2D). So far, the number of polymorphisms in SLC22A1, SLC22A2, and SLC47A1 genes coding for organic cation transporter 1 (OCT1), OCT2, and multidrug and toxin extrusion transporter 1 (MATE1) metformin transporters have been described in association with the efficacy of metformin. However, there is no information on the influence of genetic variations within these genes on the side effects of metformin. In this study, we assessed whether five single-nucleotide polymorphisms and two indel polymorphisms are associated with the side effects of metformin in patients with T2D.


METHODS
Seven polymorphisms in OCT1, OCT2, and MATE1 genes were compared between 53 T2D patients with side effects of metformin and 193 metformin users without symptoms of metformin intolerance.


RESULTS
We found a statistically significant association between the A allele of the rs628031 (P=0.012, odds ratio=0.389, confidence interval 95% [0.186-0.815]) as well as 8 bp insertion (rs36056065) in the OCT1 gene (P=0.002, odds ratio=0.405, confidence interval 95% [0.226-0.724]) and the presence of the side effects of metformin.


CONCLUSIONS
Two genetic variations in OCT1 that are in strong linkage disequilibrium may predispose toward an increased prevalence of the side effects of metformin in patients with T2D.
Latvian Biomedical Research and Study Centre, University of Latvia, Riga, Latvia.
Linda
L
Tarasova
Ineta
I
Kalnina
Kristine
K
Geldnere
Alda
A
Bumbure
Rota
R
Ritenberga
Liene
L
Nikitina-Zake
Davids
D
Fridmanis
Iveta
I
Vaivade
Valdis
V
Pirags
Janis
J
Klovins
D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D041981:Gastrointestinal Tract / Q000473:pathology*; D056726:Genetic Association Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; D008687:Metformin