Genetic analysis of SLC47A1, SLC22A1, SLC22A2, ATM gene polymorphisms among diabetics in an Indian population
DOI:
https://doi.org/10.18203/2319-2003.ijbcp20202189Keywords:
Diabetes, Metformin, Transporter gene, PolymorphismAbstract
Background: Metformin is a first-line therapy for type 2 diabetes mellitus. However, the glycaemic response to metformin is likely to be affected by polymorphisms of transporter genes. Therefore, the study was done with the aim to assess demographic distribution of transporter genotypes involved in disposition and action of metformin.
Methods: This cross-sectional, observational, single centre, clinical study was conducted in 80 diabetic patients recruited from medicine OPD. Descriptive analysis was done for distribution of the four transporter genotypes viz. SLC47A1 (rs2289669), ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342). Genotyping was determined by DNA extraction, agarose gel electrophoresis, estimation of DNA concentration, polymerase chain reaction, DNA sequencing, sequencing analysis.
Results: Transporter genotype analysis showed that for SLC47A1 (rs2289669) transporter, 31.25% and 26.25% were homozygous for AA and GG allele respectively, while 42.5% were heterozygous (AG). For ATM (rs11212617), SLC22A2 (rs316019) and SLC22A1 (rs622342) transporter, 45% and 10%, 1.25% and 80%, 58.75% and 7.50% were homozygous for AA and CC allele respectively; while 45%, 18.75%, 33.75% were heterozygous (AC) respectively. Interethnic differences in the genotype and allele frequencies of SLC22A1 (rs622342) and ATM (rs11212617) gene polymorphism were observed when compared with other major populations.
Conclusions: In the genotypic distribution of four transporter genotype study showed that there was an ethnic variation in allelic distribution of allele A and C of ATM (rs11212617) and SLC22A1 (rs622342) while AA genotype of SLC22A2 (rs316019) was rare genotype and allele ‘A’ was major allele found in our study. The study data observed would justify further pharmacogenetic studies to evaluate the role of gene polymorphism in the therapeutic efficacy of metformin.
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References
Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res. 2008;5:157-67.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81-98.
Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005;70:1851-60.
Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, et al. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009;50:1227-40.
Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK, et al. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenetics Genom. 2009;19(7):497-504.
Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22:820-7.
Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117:1422-31.
Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, et al. Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther. 2009;329:185-91.
Sato T, Masuda S, Yonezawa A, Tanihara Y, Katsura T, Inui K. Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters hOCT1/hMATE1 and hOCT2/hMATE1. Biochem Pharmacol. 2008;76:894-903.
Bachmakov I, Glaeser H, Fromm MF, Konig J. Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypeptides and organic cation transporter 1. Diabetes. 2008;57:1463-9.
Creight MLJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426-35.
Todd JN, Florez JC. An update on the pharmacogenomics of metformin: progress, problems and potential. Pharmacogenomics. 2014;15(4):529-39.
Yoon H, Cho HY, Yoo HD, Kim SM, Lee YB. Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects. AAPS J. 2013;15(2):571-80.
Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate. Science. 1998;281:363-5.
Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA. 1977;74:5463-7.
Becker ML, Visser LE, Schaik VRH, Hofman A, Uitterlinden AG, Stricker BH. Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics. 2010;20(1):38-44.
Xiao D, Guo Y, Li X, Yin JY, Zheng W, Qiu XW, et al. The Impacts of SLC22A1 rs594709 and SLC47A 1rs2289669 Polymorphisms on Metformin Therapeutic Efficacy in Chinese Type 2 Diabetes Patients. Int J Endocrinology. 2016;2016:4350712.
Vilvanathan S, Gurusamy U, Mukta V, Das A, Chandrasekaran A. Allele and genotype frequency of a genetic variant in ataxia telangiectasia mutated gene affecting glycemic response to metformin in South Indian population. Indian J Endocrinology Metabolism. 2014;18(6):850.
Islam T, Rahman MS, Paul N, Akhteruzzaman S, Sajib AA. Allele-Specific Detection of SLC22A2 rs316019 Variants Associated with Metformin Disposition through the Kidney. Int J Diabetes Metabolism. 2018:22-8.
Umamaheswaran G, Arunkumar A, Shewade D, Praveen R, Das A, Adithan C. Genetic analysis of OCT1 gene polymorphisms in an Indian population. Indian J Human Genetics. 2011;17(3):164.
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