This study sought to identify potential pharmacogenetic associations of selected enzymes and transporters with type 2 diabetes (T2D). In addition, pharmacogenomic profiles, concentrations of asymmetric dimethylarginine (ADMA) or kidney injury molecule-1 (KIM-1), and several covariates were investigated.
Whole blood was collected from 63 patients, with 32 individuals with T2D. A pharmacogenomic panel was used to assay genetic profiles, and biomarker ELISAs were run to determine subject concentrations of ADMA and KIM-1. Additive genetic modeling with multiple linear and logistic regressions were performed to discover potential SNPs-outcome associations using PLINK.
Ten SNPs were found to be significant (p<0.05) depending on the inclusion or exclusion of covariates. Of these, four were found in association with the presence of T2D, rs2231142, rs1801280, rs1799929, and rs1801265 depending on covariate inclusion or exclusion. Regarding ADMA, one SNP was found to be significant without covariates, rs1048943. Five SNPs were identified in association with KIM-1 and T2D in the presence of covariates, rs12208357, rs34059508, rs1058930, rs1902023, and rs3745274. Biomarker concentrations were not significantly different in the presence of T2D.
This exploratory study found several SNPs related to T2D; further research is required to validate and understand these relationships.
Funding source: East Tennessee State University
Award Identifier / Grant number: Unassigned
Research funding: We would like to thank Dr. Peter Panus for his assistance with statistical analysis. This study was funded in part by a Research and Development Committee Interdisciplinary Grant from East Tennessee State University.
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: Not applicable.
Ethical approval: The local Institutional Review Board deemed the study exempt from review.
1. Jaacks, LM, Siegel, KR, Gujral, UP, Narayan, KM. Type 2 diabetes: a 21st century epidemic. Best Pract Res Clin Endocrinol Metabol 2016;30:331–43. https://doi.org/10.1016/j.beem.2016.05.003.Search in Google Scholar
5. Brownrigg, JR, Hughes, CO, Burleigh, D, Karthikesalingam, A, Patterson, BO, Holt, PJ, et al.. Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. Lancet Diabetes Endocrinol 2016;4:588–97. https://doi.org/10.1016/s2213-8587(16)30057-2.Search in Google Scholar
6. Tancredi, M, Rosengren, A, Svensson, AM, Kosiborod, M, Pivodic, A, Gudbjörnsdottir, S, et al.. Excess mortality among persons with type 2 diabetes. N Engl J Med 2015;373:1720–32. https://doi.org/10.1056/nejmoa1504347.Search in Google Scholar
7. Girman, CJ, Kou, TD, Brodovicz, K, Alexander, CM, O’Neill, EA, Engel, S, et al.. Risk of acute renal failure in patients with type 2 diabetes mellitus. Diabet Med 2012;29:614–21. https://doi.org/10.1111/j.1464-5491.2011.03498.x.Search in Google Scholar PubMed
8. Zhang, D, Han, QX, Wu, MH, Shen, WJ, Yang, XL, Guo, J, et al.. Diagnostic value of sensitive biomarkers for early kidney damage in diabetic patients with normoalbuminuria. Chin Med J (Engl). 2018;131:2891–2.Search in Google Scholar
9. Konya, H, Miuchi, M, Satani, K, Matsutani, S, Yano, Y, Tsunoda, T, et al.. Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus. World J Exp Med 2015;5:110–9. https://doi.org/10.5493/wjem.v5.i2.110.Search in Google Scholar PubMed PubMed Central
10. Zhou, S, Zhu, Q, Li, X, Chen, C, Liu, J, Ye, Y, et al.. Asymmetric dimethylarginine and all-cause mortality: a systematic review and meta-analysis. Sci Rep 2017;7:44692. https://doi.org/10.1038/srep44692.Search in Google Scholar PubMed PubMed Central
11. Song, J, Yu, J, Prayogo, GW, Cao, W, Wu, Y, Jia, Z, et al.. Understanding kidney injury molecule 1: a novel immune factor in kidney pathophysiology. Am J Transl Res 2019;11:1219–29.Search in Google Scholar
12. Zhang, Z, Cai, CX. Kidney injury molecule-1 (KIM-1) mediates renal epithelial cell repair via ERK MAPK signaling pathway. Mol Cell Biochem 2016;416:109–16. https://doi.org/10.1007/s11010-016-2700-7.Search in Google Scholar PubMed PubMed Central
13. Huang, C, Florez, JC. Pharmacogenetics in type 2 diabetes: potential implications for clinical practice. Genome Med 2011;3:76. https://doi.org/10.1186/gm292.Search in Google Scholar PubMed PubMed Central
15. Azarova, I, Bushueva, O, Konoplya, A, Polonikov, A. Glutathione S-transferase genes and the risk of type 2 diabetes mellitus: role of sexual dimorphism, gene-gene and gene-smoking interactions in disease susceptibility. J Diabetes 2018;10:398–407. https://doi.org/10.1111/1753-0407.12623.Search in Google Scholar PubMed
16. Yamada, Y, Matsuo, H, Watanabe, S, Kato, K, Yajima, K, Hibino, T, et al.. Association of a polymorphism of CYP3A4 with type 2 diabetes mellitus. Int J Mol Med 2007;20:703–7.Search in Google Scholar
17. Xie, F, Chan, JC, Ma, RC. Precision medicine in diabetes prevention, classification and management. J Diabetes Investig 2018;9:998–1015. https://doi.org/10.1111/jdi.12830.Search in Google Scholar PubMed PubMed Central
18. Schaller, L, Lauschke, VM. The genetic landscape of the human solute carrier (SLC) transporter superfamily. Hum Genet 2019;138:1359–77. https://doi.org/10.1007/s00439-019-02081-x.Search in Google Scholar PubMed PubMed Central
19. Kawaguchi-Suzuki, M, Frye, RF. Current clinical evidence on pioglitazone pharmacogenomics. Front Pharmacol 2013;4:147. https://doi.org/10.3389/fphar.2013.00147.Search in Google Scholar PubMed PubMed Central
20. Aquilante, CL. Sulfonylurea pharmacogenomics in type 2 diabetes: the influence of drug target and diabetes risk polymorphisms. Expert Rev Cardiovasc Ther 2010;8:359–72. https://doi.org/10.1586/erc.09.154.Search in Google Scholar PubMed PubMed Central
21. Murrell, DE, Cluck, DB, Moorman, JP, Brown, SD, Wang, KS, Duffourc, MM, et al.. HIV integrase inhibitor pharmacogenetics: an exploratory study. Clin Drug Investig 2019;39:285–99. https://doi.org/10.1007/s40261-018-0739-9.Search in Google Scholar PubMed
22. Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MA, Bender, D, et al.. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559–75. https://doi.org/10.1086/519795.Search in Google Scholar PubMed PubMed Central
23. Woodward, OM, Köttgen, A, Coresh, J, Boerwinkle, E, Guggino, WB, Köttgen, M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci U S A 2009;106:10338–42. https://doi.org/10.1073/pnas.0901249106.Search in Google Scholar PubMed PubMed Central
24. Matsuo, H, Ichida, K, Takada, T, Nakayama, A, Nakashima, H, Nakamura, T, et al.. Common dysfunctional variants in ABCG2 are a major cause of early-onset gout. Sci Rep 2013;3:2014. https://doi.org/10.1038/srep02014.Search in Google Scholar PubMed PubMed Central
25. Wen, CC, Yee, SW, Liang, X, Hoffmann, TJ, Kvale, MN, Banda, Y, et al.. Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther 2015;97:518–25. https://doi.org/10.1002/cpt.89.Search in Google Scholar PubMed PubMed Central
26. DeGorter, MK, Tirona, RG, Schwarz, UI, Choi, YH, Dresser, GK, Suskin, N, et al.. Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care. Circ Cardiovasc Genet 2013;6:400–8. https://doi.org/10.1161/circgenetics.113.000099.Search in Google Scholar
27. Zhu, Y, Hu, Y, Huang, T, Zhang, Y, Li, Z, Luo, C, et al.. High uric acid directly inhibits insulin signalling and induces insulin resistance. Biochem Biophys Res Commun 2014;447:707–14. https://doi.org/10.1016/j.bbrc.2014.04.080.Search in Google Scholar PubMed
28. McDonagh, EM, Boukouvala, S, Aklillu, E, Hein, DW, Altman, RB, Klein, TE. PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenetics Genom 2014;24:409–25. https://doi.org/10.1097/fpc.0000000000000062.Search in Google Scholar
29. Al-Shaqha, WM, Alkharfy, KM, Al-Daghri, NM, Mohammed, AK. N-acetyltransferase 1 and 2 polymorphisms and risk of diabetes mellitus type 2 in a Saudi population. Ann Saudi Med 2015;35:214–21. https://doi.org/10.5144/0256-4947.2015.214.Search in Google Scholar PubMed PubMed Central
30. Knowles, JW, Xie, W, Zhang, Z, Chennamsetty, I, Chennemsetty, I, Paananen, J, et al.. Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. J Clin Invest 2015;125:1739–51. https://doi.org/10.1172/jci74692.Search in Google Scholar
31. Hein, DW, Fretland, AJ, Doll, MA. Effects of single nucleotide polymorphisms in human N-acetyltransferase 2 on metabolic activation (O-acetylation) of heterocyclic amine carcinogens. Int J Cancer 2006;119:1208–11. https://doi.org/10.1002/ijc.21957.Search in Google Scholar PubMed PubMed Central
32. Walraven, JM, Zang, Y, Trent, JO, Hein, DW. Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2. Curr Drug Metabol 2008;9:471–86. https://doi.org/10.2174/138920008784892065.Search in Google Scholar PubMed PubMed Central
33. Zang, Y, Doll, MA, Zhao, S, States, JC, Hein, DW. Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis 2007;28:1665–71. https://doi.org/10.1093/carcin/bgm085.Search in Google Scholar PubMed PubMed Central
34. Sabbagh, A, Langaney, A, Darlu, P, Gérard, N, Krishnamoorthy, R, Poloni, ES. Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. BMC Genet 2008;9:21. https://doi.org/10.1186/1471-2156-9-21.Search in Google Scholar PubMed PubMed Central
35. Amstutz, U, Henricks, LM, Offer, SM, Barbarino, J, Schellens, JHM, Swen, JJ, et al.. Clinical pharmacogenetics implementation consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther 2018;103:210–6. https://doi.org/10.1002/cpt.911.Search in Google Scholar PubMed PubMed Central
36. He, YF, Wei, W, Zhang, X, Li, YH, Li, S, Wang, FH, et al.. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in Chinese cancer patients. J Clin Pharm Therapeut 2008;33:307–14. https://doi.org/10.1111/j.1365-2710.2008.00898.x.Search in Google Scholar PubMed
37. Kisselev, P, Schunck, WH, Roots, I, Schwarz, D. Association of CYP1A1 polymorphisms with differential metabolic activation of 17beta-estradiol and estrone. Cancer Res 2005;65:2972–8. https://doi.org/10.1158/0008-5472.can-04-3543.Search in Google Scholar PubMed
38. Lozano, E, Herraez, E, Briz, O, Robledo, VS, Hernandez-Iglesias, J, Gonzalez-Hernandez, A, et al.. Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. BioMed Res Int 2013;2013:692071. https://doi.org/10.1155/2013/692071.Search in Google Scholar PubMed PubMed Central
39. Matthaei, J, Kuron, D, Faltraco, F, Knoch, T, Dos Santos Pereira, JN, Abu Abed, M, et al.. OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymorphisms affect sumatriptan pharmacokinetics. Clin Pharmacol Ther 2016;99:633–41. https://doi.org/10.1002/cpt.317.Search in Google Scholar PubMed
40. Tzvetkov, MV, Matthaei, J, Pojar, S, Faltraco, F, Vogler, S, Prukop, T, et al.. Increased systemic exposure and stronger cardiovascular and metabolic adverse reactions to fenoterol in individuals with heritable OCT1 deficiency. Clin Pharmacol Ther 2018;103:868–78. https://doi.org/10.1002/cpt.812.Search in Google Scholar PubMed
41. Shu, Y, Leabman, MK, Feng, B, Mangravite, LM, Huang, CC, Stryke, D, et al.. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci U S A 2003;100:5902–7. https://doi.org/10.1073/pnas.0730858100.Search in Google Scholar PubMed PubMed Central
42. Liang, X, Yee, SW, Chien, HC, Chen, EC, Luo, Q, Zou, L, et al.. Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content. PLoS Biol 2018;16:e2002907. https://doi.org/10.1371/journal.pbio.2002907.Search in Google Scholar PubMed PubMed Central
43. Papageorgiou, I, Court, MH. Identification and validation of the microRNA response elements in the 3’-untranslated region of the UDP glucuronosyltransferase (UGT) 2B7 and 2B15 genes by a functional genomics approach. Biochem Pharmacol 2017;146:199–213. https://doi.org/10.1016/j.bcp.2017.09.013.Search in Google Scholar PubMed PubMed Central
44. Court, MH, Zhu, Z, Masse, G, Duan, SX, James, LP, Harmatz, JS, et al.. Race, gender, and genetic polymorphism contribute to variability in acetaminophen pharmacokinetics, metabolism, and protein-adduct concentrations in healthy African-American and European-American volunteers. J Pharmacol Exp Therapeut 2017;362:431–40. https://doi.org/10.1124/jpet.117.242107.Search in Google Scholar PubMed PubMed Central
45. Mijderwijk, H, Klimek, M, van Beek, S, van Schaik, RH, Duivenvoorden, HJ, Stolker, RJ. Implication of UGT2B15 genotype polymorphism on postoperative anxiety levels in patients receiving lorazepam premedication. Anesth Analg 2016;123:1109–15. https://doi.org/10.1213/ane.0000000000001508.Search in Google Scholar PubMed
46. Kim, JY, Cheong, HS, Park, BL, Kim, LH, Namgoong, S, Kim, JO, et al.. Comprehensive variant screening of the UGT gene family. Yonsei Med J 2014;55:232–9. https://doi.org/10.3349/ymj.2014.55.1.232.Search in Google Scholar PubMed PubMed Central
47. Backman, JT, Filppula, AM, Niemi, M, Neuvonen, PJ. Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev 2016;68:168–241. https://doi.org/10.1124/pr.115.011411.Search in Google Scholar PubMed
48. Daily, EB, Aquilante, CL. Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics 2009;10:1489–510. https://doi.org/10.2217/pgs.09.82.Search in Google Scholar PubMed PubMed Central
49. Lazarska, KE, Dekker, SJ, Vermeulen, NPE, Commandeur, JNM. Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism. Toxicol Lett 2018;284:70–8. https://doi.org/10.1016/j.toxlet.2017.11.038.Search in Google Scholar PubMed
50. Sánchez-Martín, A, Cabrera Figueroa, S, Cruz, R, Porras-Hurtado, L, Calvo-Boyero, F, Rasool, M, et al.. Gene-gene interactions between DRD3, MRP4 and CYP2B6 polymorphisms and its influence on the pharmacokinetic parameters of efavirenz in HIV infected patients. Drug Metabol Pharmacokinet 2016;31:349–55. https://doi.org/10.1016/j.dmpk.2016.06.001.Search in Google Scholar PubMed
51. Giacomelli, A, Rusconi, S, Falvella, FS, Oreni, ML, Cattaneo, D, Cozzi, V, et al.. Clinical and genetic determinants of nevirapine plasma trough concentration. SAGE Open Med 2018;6:2050312118780861. https://doi.org/10.1177/2050312118780861.Search in Google Scholar PubMed PubMed Central
52. Lin, KY, Ito, A, Asagami, T, Tsao, PS, Adimoolam, S, Kimoto, M, et al.. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002;106:987–92. https://doi.org/10.1161/01.cir.0000027109.14149.67.Search in Google Scholar PubMed
53. Khan, FA, Fatima, SS, Khan, GM, Shahid, S. Evaluation of kidney injury molecule-1 as a disease progression biomarker in diabetic nephropathy. Pakistan J Med Sci 2019;35:992–6.Search in Google Scholar
54. Carlsson, AC, Calamia, M, Risérus, U, Larsson, A, Helmersson-Karlqvist, J, Lind, L, et al.. Kidney injury molecule (KIM)-1 is associated with insulin resistance: results from two community-based studies of elderly individuals. Diabetes Res Clin Pract 2014;103:516–21. https://doi.org/10.1016/j.diabres.2013.12.008.Search in Google Scholar PubMed
The online version of this article offers supplementary material (https://doi.org/10.1515/dmpt-2021-0135).
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