Genetic Variants of CYP2C8 Gene Predisposition to Type 2 Diabetes Risk
Saleh Abd-Qader Abed 1, Ammar Ahmed Sultan 1*
Journal of Angiotherapy 8(2) 1-9 https://doi.org/10.25163/angiotherapy.829493
Submitted: 01 January 2024 Revised: 26 February 2024 Published: 29 February 2024
This study determined the genetic variations in the CYP2C8 gene which may illuminate predispositions to type 2 diabetes.
Abstract
Background: Type 2 diabetes mellitus (T2DM) is characterized by elevated blood glucose levels due to insulin resistance or inadequate insulin secretion from pancreatic beta cells. The mitochondrial CYP2C8 gene, located on chromosome 10q24, encodes cytochrome P450 and spans 37 kb with nine exons. Genetic variants in this gene may influence T2DM susceptibility. Method: This study aimed to investigate the association between genetic polymorphisms in the CYP2C8 gene (rs1934953 and rs1934952) and the risk of T2DM in Iraqi patients. Blood samples were collected from 48 participants, including 24 T2DM patients and 24 healthy controls. DNA extraction, polymerase chain reaction (PCR), and sequencing were performed to analyze genetic variations. Statistical analysis was conducted using chi-square tests, logistic regression, and Hardy-Weinberg equilibrium calculations. Results: Analysis revealed that the rs1934953 variant in the CYP2C8 gene was associated with T2DM, with the A allele showing a protective effect (odds ratio: 0.840, 95% confidence interval: 0.780-0.904, P=3.04×10-6). Additionally, an interaction effect between rs1934953 in CYP2C9 and rs12766752 in CYP2C8 on T2DM risk was observed (P=0.003). Furthermore, rs1934953 showed significant association with high-density lipoprotein cholesterol (HDL-C). At the rs1934952 C/T locus, a transition type genetic mutation was detected, with the TT genotype considered a risk factor for T2DM, while the CC and CT genotypes were protective. The Hardy-Weinberg probability value for the patient group was 0.0321, indicating notable discrepancies in genotype distribution, while the healthy group showed no significant differences (Hardy probability: 0.2001). The TT genotype at rs1934953 was associated with a decreased risk of T2DM, while the CC and CT genotypes were potential risk factors. Conversely, at rs1934952, the CC and CT genotypes were protective against T2DM, while the TT genotype was associated with increased risk. Conclusion: in conclusion, the study indicates that there may be links between CYP2C8 gene variances and an increased chance of type 2 diabetes in Iraqi patients.
Keywords: Cytochrome P450, Translocation, Odds ratio, Type 2 diabetes mellitus (T2DM), CYP2C8 gene, Genetic polymorphisms, Insulin resistance, Epidemiological analysis
References
Abbasi, A., Corpeleijn, E., Gansevoort, R. T., Gans, R. O., Hillege, H. L., Stolk, R. P., … & Dullaart, R. P. (2013). Role of HDL cholesterol and estimates of HDL particle composition in future development of type 2 diabetes in the general population: the PREVEND study. The Journal of Clinical Endocrinology & Metabolism, 98(8), E1352-E1359.
Altalalgah, M. N; and Thalathini, M. (2018). Genetic Polymorphism and Risk of having Type 2 Diabetes in a Palestinian Population: A Study of 16 Gene Polymorphisms. Insulin, 3, 2.
Alzubadiy , M. W. M., Almohaidi, A. M. S., Sultan, A. A., & Abdulhameed, L. Q. (2019, September). Evaluation of E-selectin rs 5367 C/T Polymorphism in Iraqi Diabetic Foot patients. In Journal of Physics: Conference Series (Vol. 1294, No. 6, p. 062021). IOP Publishing.
Aquilante, C. L; Bushman, L. R; Knutsen, S. D; Burt, L. E; Rome, L. C; and Kosmiski, L. A. (2008). Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers. Human genomics, 3(1), 7.
Coward, R. J., Welsh, G. I., Yang, J., Tasman, C., Lennon, R., Koziell, A., & Saleem, M. A. (2005). The human glomerular podocyte is a novel target for insulin action. Diabetes, 54(11), 3095-3102
Davies, M. J: Aroda, V. R; Collins, B. S; Gabbay, R. A; Green, J., Maruthur, N. M.,... and Buse, J. B. (2022). Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia, 65(12), 1925-1966
Dawed, A. Y., Donnelly, L., Tavendale, R., Carr, F., Leese, G., Palmer, C. N., … & Zhou, K. (2016). CYP2C8 and SLCO1B1 variants and therapeutic response to thiazolidinediones in patients with type 2 diabetes. Diabetes care, 39(11), 1902-1908.
El Banna, D. A; Fareed, M. E; and Abd-Elalem, S. M. (2021). Effect of Selected Range of Motion Exercise on Peripheral Circulation among Patients with Type II Diabetes Mellitus. Menoufia Nursing Journal, 6(2), 35-49.
Gangadhariah, M. H., Dieckmann, B. W., Lantier, L., Kang, L., Wasserman, D. H., Chiusa, M., … & Luther, J. M. (2017). Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia, 60, 1066-1075.
Gutt, M., Davis, C. L., Spitzer, S. B., Llabre, M. M., Kumar, M., Czarnecki, E. M., … & Marks, J. B. (2000). Validation of the insulin sensitivity index (ISI0, 120): comparison with other measures. Diabetes research and clinical practice, 47(3), 177-184.
Harrow, J., Frankish, A., Gonzalez, J. M., Tapanari, E., Diekhans, M., Kokocinski, F.,... and Hubbard, T. J. (2012). GENCODE: the reference human genome annotation for The ENCODE Project. Genome research, 22(9), 1760-1774.
Hertz, D. L., Roy, S., Motsinger-Reif, A. A., Drobish, A., Clark, L. S., McLeod, H. L., … & Dees, E. (2013). CYP2C8* 3 increases risk of neuropathy in breast cancer patients treated with paclitaxel. Annals of oncology, 24(6), 1472-1478.
Holstein, A., Plaschke, A., Ptak, M., Egberts, E. H., El-Din, J., Brockmoeller, J., & Kirchheiner, J. (2005). Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents. British journal of clinical pharmacology, 60(1), 103-106.
Hu, C., & Jia, W. (2018). Diabetes in China: epidemiology and genetic risk factors and their clinical utility in personalized medication. Diabetes, 67(1), 3-11.
Kim, S. K., & Novak, R. F. (2007). The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacology & therapeutics, 113(1), 88-120.
Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985). Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412-419.
Meo, S. A., Memon, A. N., Sheikh, S. A., Rouq, F. A., Usmani, A. M., Hassan, A., & Arian, S. A. (2015). Effect of environmental air pollution on type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci, 19(1), 123-128.
Niemi, M., Leathart, J. B., Neuvonen, M., Backman, J. T., Daly, A. K., & Neuvonen, P. J. (2003). Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide. Clinical Pharmacology & Therapeutics, 74(4), 380-387.
Ragia, G., Petridis, I., Tavridou, A., Christakidis, D., & Manolopoulos, V. G. (2009). Presence of CYP2C9* 3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics, 10(11), 1781-1787.
Rawshani, A., & Gudbjörnsdottir, S. (2018). Smoking and Other Risk Factors in Type 2 Diabetes. The New England Journal of Medicine, 379(26), 2575-2575.
Schäfer, A., Neschen, S., Kahle, M., Sarioglu, H., Gaisbauer, T., Imhof, A., … & Ueffing, M. (2015). The epoxyeicosatrienoic acid pathway enhances hepatic insulin signaling and is repressed in insulin-resistant mouse liver. Molecular & Cellular Proteomics, 14(10), 2764-2774.
Shahabi, P., Siest, G., Meyer, U. A., & Visvikis-Siest, S. (2014). Human cytochrome P450 epoxygenases: variability in expression and role in inflammation-related disorders. Pharmacology & therapeutics, 144(2), 134-161.
Stage, T. B; Christensen, M. M; Feddersen, S; Beck-Nielsen, H; and Brøsen, K. (2013). The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes. Pharmacogenetics and genomics, 23(4), 219-227.
Stumvoll, M., Van Haeften, T., Fritsche, A., & Gerich, J. (2001). Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times. Diabetes care, 24(4), 796.
Takano, C; Ogawa, E; and Hayakawa, S. (2023). Insulin resistance in mitochondrial diabetes. Biomolecules, 13(1), 126.
Tayek, C. J; Cherukuri, L; Hamal, S; and Tayek, J. A. (2018). Importance of fasting blood glucose goals in the management of type 2 diabetes mellitus: a review of the literature and a critical appraisal. Journal of diabetes, metabolic disorders and control, 5(4), 113.
Wang, L., Gao, P., Zhang, M., Huang, Z., Zhang, D., Deng, Q., … & Wang, L. (2017). Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. Jama, 317(24), 2515-2523..
Xu, X., Li, R., Chen, G., Hoopes, S. L., Zeldin, D. C., & Wang, D. W. (2016). The role of cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids in metabolic diseases. Advances in nutrition, 7(6), 1122-1128.
Yamoune, S., Wintz, K., Niederau, C., Craveiro, R. B., Wolf, M., and Stingl, J. (2022). Role of cytochrome P450 2C8 genetic polymorphism and epoxygenase uncoupling in periodontal remodelling affecting orthodontic treatment. Basic and Clinical Pharmacology and Toxicology, 130(1), 132-140.
Zimmet, P., Shi, Z., El-Osta, A., & Ji, L. (2018). Epidemic T2DM, early development and epigenetics: implications of the Chinese Famine. Nature Reviews Endocrinology, 14(12), 738-746.
View Dimensions
View Altmetric
Save
Citation
View
Share