Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-term response to metformin monotherapy in type 2 diabetes mellitus patients.
OBJECTIVE
High variability in clinical response to metformin is often observed in type 2 diabetes (T2D) patients, and it highlights the need for identification of genetic components affecting the efficiency of metformin therapy. Aim of this observational study is to evaluate the role of tagSNPs (tagging single nucleotide polymorphisms) from genomic regions coding for six metformin transporter genes with respect to the short-term efficiency.


METHODS
102 tagSNPs in 6 genes coding for metformin transporters were genotyped in the group of 102 T2D patients treated with metformin for 3 months.


METHODS
Most significant hits were analyzed in the group of 131 T2D patients from Slovakia. Pharmacokinetic study in 25 healthy nondiabetic volunteers was conducted to investigate the effects of identified polymorphisms.


RESULTS
In the discovery group of 102 patients, minor alleles of rs3119309, rs7757336 and rs2481030 were significantly nominally associated with metformin inefficiency (P = 1.9 × 10-6to 8.1 × 10-6). Effects of rs2481030 and rs7757336 did not replicate in the group of 131 T2DM patients from Slovakia alone, whereas rs7757336 was significantly associated with a reduced metformin response in combined group. In pharmacokinetic study, group of individuals harboring risk alleles of rs7757336 and rs2481030 displayed significantly reduced AUC∞of metformin in plasma.


CONCLUSIONS
For the first time, we have identified an association between the lack of metformin response and SNPs rs3119309 and rs7757336 located in the 5' flanking region of the genes coding for Organic cation transporter 2 and rs2481030 located in the 5' flanking region of Organic cation transporter 3 that was supported by the results of a pharmacokinetic study on 25 healthy volunteers.
Latvian Biomedical Research and Study CentreRiga, Latvia.
Linda
L
Zaharenko
Latvian Biomedical Research and Study CentreRiga, Latvia.
Ineta
I
Kalnina
Pauls Stradins Clinical University HospitalRiga, Latvia.|Faculty of MedicineUniversity of Latvia, Riga, Latvia.
Kristine
K
Geldnere
Riga East Clinical University HospitalRiga, Latvia.|Riga Stradins UniversityRiga, Latvia.
Ilze
I
Konrade
Latvian Institute of Organic SynthesisRiga, Latvia.
Solveiga
S
Grinberga
Faculty of MedicineP. J. Šafárik University, Košice, Slovakia.
Jozef
J
Židzik
Faculty of MedicineP. J. Šafárik University, Košice, Slovakia.
Martin
M
Javorský
Riga East Clinical University HospitalRiga, Latvia.|Riga Stradins UniversityRiga, Latvia.
Aivars
A
Lejnieks
Latvian Biomedical Research and Study CentreRiga, Latvia.
Liene
L
Nikitina-Zake
Latvian Biomedical Research and Study CentreRiga, Latvia.
Davids
D
Fridmanis
Latvian Biomedical Research and Study CentreRiga, Latvia.
Raitis
R
Peculis
Latvian Biomedical Research and Study CentreRiga, Latvia.
Ilze
I
Radovica-Spalvina
Latvian Institute of Organic SynthesisRiga, Latvia.
Dace
D
Hartmane
Latvian Institute of Organic SynthesisRiga, Latvia.
Osvalds
O
Pugovics
Faculty of MedicineP. J. Šafárik University, Košice, Slovakia.
Ivan
I
Tkáč
Faculty of MedicineP. J. Šafárik University, Košice, Slovakia.
Lucia
L
Klimčáková
Pauls Stradins Clinical University HospitalRiga, Latvia.|Faculty of MedicineUniversity of Latvia, Riga, Latvia.
Valdis
V
Pīrāgs
Latvian Biomedical Research and Study CentreRiga, Latvia klovins@biomed.lu.lv.
Janis
J
Klovins
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000627:therapeutic use; D008687:Metformin / Q000097:blood* / Q000627:therapeutic use; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D000099254:Organic Cation Transporter 3
D007004:Hypoglycemic Agents; D008687:Metformin; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D000099254:Organic Cation Transporter 3; C491013:SLC22A2 protein, human