Abstract
Objectives
Hypoglycemia is the most common adverse effect of sulfonylureas (SUs) and a major concern when using these drugs. Transcription factor 7-like 2 (TCF7L2) rs7903146 C>T polymorphism is an established and well characterized genetic marker of type 2 diabetes (T2DM) risk. The aim of the present study was to analyze the potential association of TCF7L2 rs7903146 C>T polymorphism with SU-induced hypoglycemia in a well characterized cohort of SU-treated patients previously genotyped for cytochrome P450 2C9 (CYP2C9) and P450 oxidoreductase (POR).
Methods
The study group consisted of 176 SU-treated T2DM patients of whom 92 had experienced at least one drug-associated hypoglycemic event. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for TCF7L2 rs7903146 genotyping.
Results
TCF7L2 rs7903146 C>T genotype and allele frequency did not differ between cases and controls (p=0.745 and 0.671, respectively). In logistic regression analysis adjusted for other factors affecting hypoglycemia, including CYP2C9 and POR genotypes, TCF7L2 rs7903146 C>T polymorphism did not increase the risk of hypoglycemia (OR=1.238, 95% C.I.=0.750–2.044, p=0.405).
Conclusions
TCF7L2 rs7903146 C>T polymorphism is not associated with SU-induced hypoglycemia. Identifying additional gene polymorphisms associated with SU-induced hypoglycemia is crucial for improving T2DM patient therapy with SUs.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The study protocol was approved by the Scientific Council and the Ethics Committee of the Academic General Hospital of Alexandroupolis and was conducted according to Declaration of Helsinki.
References
1. Manolopoulos, VG, Ragia, G, Tavridou, A. Pharmacogenomics of oral antidiabetic medications: current data and pharmacoepigenomic perspective. Pharmacogenomics 2011;12:1161–91. https://doi.org/10.2217/pgs.11.65.Search in Google Scholar PubMed
2. Schopman, JE, Simon, AC, Hoefnagel, SJ, Hoekstra, JB, Scholten, RJ, Holleman, F. The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev 2014;30:11–22. https://doi.org/10.1002/dmrr.2470.Search in Google Scholar PubMed
3. Holstein, A, Plaschke, A, Ptak, M, Egberts, EH, El-Din, J, Brockmöller, J, et al.. Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents. Br J Clin Pharmacol 2005;60:103–6. https://doi.org/10.1111/j.1365-2125.2005.02379.x.Search in Google Scholar PubMed PubMed Central
4. Ragia, G, Petridis, I, Tavridou, A, Christakidis, D, Manolopoulos, VG. Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics 2009;10:1781–7. https://doi.org/10.2217/pgs.09.96.Search in Google Scholar PubMed
5. Gökalp, O, Gunes, A, Cam, H, Cure, E, Aydın, O, Tamer, MN, et al.. Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting. Eur J Clin Pharmacol 2011;67:1223–9. https://doi.org/10.1007/s00228-011-1078-4.Search in Google Scholar PubMed
6. Saberi, M, Ramazani, Z, Rashidi, H, Saberi, A. The effect of CYP2C9 genotype variants in type 2 diabetes on the pharmacological effectiveness of sulfonylureas, diabetic retinopathy, and nephropathy. Vasc Health Risk Manag 2020;16:241–8. https://doi.org/10.2147/vhrm.s230639.Search in Google Scholar PubMed PubMed Central
7. Klen, J, Dolžan, V, Janež, A. CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients. Eur J Clin Pharmacol 2014;70:421–8. https://doi.org/10.1007/s00228-014-1641-x.Search in Google Scholar PubMed
8. Ragia, G, Tavridou, A, Elens, L, Van Schaik, RH, Manolopoulos, VG. CYP2C9*2 allele increases risk for hypoglycemia in POR*1/*1 type 2 diabetic patients treated with sulfonylureas. Exp Clin Endocrinol Diabetes 2014;122:60–3. https://doi.org/10.1055/s-0033-1361097.Search in Google Scholar PubMed
9. Dujic, T, Zhou, K, Donnelly, LA, Leese, G, Palmer, CNA, Pearson, ER. Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: a GoDARTS Study. Diabetes Obes Metabol 2018;20:211–4. https://doi.org/10.1111/dom.13046.Search in Google Scholar PubMed PubMed Central
10. Ding, W, Xu, L, Zhang, L, Han, Z, Jiang, Q, Wang, Z, et al.. Meta-analysis of association between TCF7L2 polymorphism rs7903146 and type 2 diabetes mellitus. BMC Med Genet 2018;19:38. https://doi.org/10.1186/s12881-018-0553-5.Search in Google Scholar PubMed PubMed Central
11. Holstein, A, Hahn, M, Körner, A, Stumvoll, M, Kovacs, P. TCF7L2 and therapeutic response to sulfonylureas in patients with type 2 diabetes. BMC Med Genet 2011;12:30. https://doi.org/10.1186/1471-2350-12-30.Search in Google Scholar PubMed PubMed Central
12. Ragia, G, Tavridou, A, Petridis, I, Manolopoulos, VG. Association of KCNJ11 E23K gene polymorphism with hypoglycemia in sulfonylurea-treated type 2 diabetic patients. Diabetes Res Clin Pract 2012;98:119–24. https://doi.org/10.1016/j.diabres.2012.04.017.Search in Google Scholar PubMed
13. Allahdini, M, Kamalidehghan, B, Akbari, L, Azadfar, P, Rahmani, A, Ahmadipour, F, et al.. Prevalence of the rs7903146C>T polymorphism in TCF7L2 gene for prediction of type 2 diabetes risk among Iranians of different ethnicities. Drug Des Dev Ther 2015;9:5835–41.10.2147/DDDT.S82485Search in Google Scholar PubMed PubMed Central
14. Pappa, KI, Gazouli, M, Economou, K, Daskalakis, G, Anastasiou, E, Anagnou, NP, et al.. Gestational diabetes mellitus shares polymorphisms of genes associated with insulin resistance and type 2 diabetes in the Greek population. Gynecol Endocrinol 2011;27:267–72. https://doi.org/10.3109/09513590.2010.490609.Search in Google Scholar PubMed
15. Katsoulis, K, Paschou, SA, Hatzi, E, Tigas, S, Georgiou, I, Tsatsoulis, A. TCF7L2 gene variants predispose to the development of type 2 diabetes mellitus among individuals with metabolic syndrome. Hormones (Basel) 2018;17:359–65. https://doi.org/10.1007/s42000-018-0047-z.Search in Google Scholar PubMed
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