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Definition of pharmacogenetic markers for the prediction of efficacy and side-effects of metformin therapy of type 2 diabetes

Funding: European Economic area project EEZ09AP-34/01

Period: 2008-2010

Subproject manager: Dr. biol. Jānis Kloviņš

Aim

The aim of this project is to carry out complex pharmacogenetic exploration of SLC22 and SLC47 transporter gene group in association with metformin efficiency in T2D patient treatment and metformin side effects. The focus of this study is to discover combinations of four genes (OCT1, OCT2, MATE1 and MATE2-K) that are related to metformin side-effects or low therapy efficiency. It is also planned to evaluate treatment efficiency of novel metformin drug forms in association of identified genetic markers to develop prognostic genetic tests for individualized T2D therapies.

Tasks

1)      To select three study groups from Latvian Genome Data Base (LGDB) and recruit new T2D patients from P.Stradina Clinical University Hospital, depending on metformin and metformin novel forms tolerance.

2)      To carry out genotyping of 10 potentially functional SNPs and 14 tagSNPs in four genes that are involved in metformin transportation and excretion - SLC22A1, SLC22A2, SLC47A1 and SLC47A2.

3)      To analyse obtained results and explore the role of polymorphisms in relation to metformin efficiency and side effects.

4)      To derive high risk polymorphisms panel for genetic testing and develop recommendations for implementation for metformin efficiency prognostic.

 Results

 The 82 T2D patients having partial or complete metformin intolerance have been included in the research. The 236 T2D patients with no metformin side effects were used as a control group.

All participants were genotyped using RT-PCR or sequencing for five SNPs in SLC22A1, SLC22A2, SLC47A1, and two deletions in gene SLC22A1.

One SNP and one deletion are significantly associated with metformin intolerance. Several haplotypes also have demonstrated association with metformin intolerance. One SNP in SLC47A1 gene have shown statistically significant association with body mass index (BMI) in patients using metformin indicating the possible effect of the polymorphism on increased activity of metformin.

The genotyping optimization of explored SNPs was carried out and the complex of genetic diagnostic test validated. That has served for development of recommendations for possible individualized metformin therapy.

 Conclusions

 The association between metformin transporter polymorphisms and efficiency and side effects of the drug, the gene to gene interaction mechanisms have also been assed.

The detailed reports of this project and publication have been prepared. The recommendations and methodology for individual metformin therapy based on genetic characteristics have been created. The minimal set of SNP for genotyping has been developed.



Mājas lapas izstrādi finansēja ERAF 2.1.1.2. aktivitātes projekts Nr. 2010/0196/2DP/2.1.1.2.0/10/APIA/VIAA/004 "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".