UTICAJ ABCG2 421 C>A I SLCO1B1 521T>C GENSKOG POLIMORFIZMA NA KONTROLU LIPIDNOG STATUSA BOLESNIKA LEČENIH ATORVASTATINOM I ROSUVASTATINOM
Sažetak
Polimorfizmi gena za transportere lekova SLCO1B1 (OATP1B1 transporter) 521T>C i ABCG2 421C>A (BCRP transporter) mogu imati uticaja na metabolizam statina i, posledično, na farmakodinamičke efekte ovih lekova. Cilj ove studije bio je da se ispita povezanost između genskih polimorfizama za transportere lekova i kontrole lipidnog statusa kod bolesnika u čijem su lečenju korišćene različite doze statina. Dodatno, poredili smo serumsku aktivnost aspartat aminotransferaze (engl. aspartate aminotransferase – AST) i alanin aminotransferaze (engl. alanine aminotransferase – ALT) kod nosilaca različitih genotipova ispitivanih polimorfizama. Farmakogenetička studija preseka obuhvatila je sto dva bolesnika sa dislipidemijom koji su bili na terapiji atorvastatinom ili rosuvastatinom najmanje četiri nedelje. Vrednosti lipidnih parametara prikupljene su prilikom rutinske kontrole bolesnika. Za ispitivanje genskih polimorfizama korišćena je metoda Real-Time PCR. Frekvencije mutiranih alela 521C i 421A bile su 32,35% i 19,61%, redom. Pokazalo se da bolesnici koji su nosioci mutiranog A-alela ABCG2 421C>A i koji uzimaju više doze atorvastatina imaju statistički značajno niže vrednosti LDL holesterola od bolesnika koji imaju wild type genotip. Osim toga, prisustvo varijantnog 521C alela SLCO1B1 polimorfizma uticalo je na bolju kontrolu serumskih vrednosti HDL holesterola kod bolesnika koji uzimaju veće doze rosuvastatina. Dobijeni rezultati nisu pokazali statistički značajnu povezanost između aktivnosti AST-a i ALT-a i ispitivanih genskih polimorfizama. Studija je pokazala da prisustvo ispitivanih genskih polimorfizama može biti povezano s kontrolom određenih “parametara lipida”. Neophodna su dalja istraživanja na većem broju ispitanika. Takođe, poželjno je određivanje koncentracije leka u krvi da bi se dobila potpunija slika o vezi između genskih polimorfizama, doze i efekta statina.
Reference
Averbukh LD, Turshudzhyan A, Wu DC, Wu GY. Statin-induced Liver Injury Patterns: A Clinical Review. J Clin Transl Hepatol 2022;10(3):543-52. [CrossRef][PubMed]
Bhardwaj SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis 2007;11(7):597–613. [CrossRef][PubMed]
Choi HY, Bae KS, Cho SH, Ghim JL, Choe S, Jung JA, et al. Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid. Pharmacogenet Genomics 2015;25(12):595-608. [CrossRef][PubMed]
Choi SA, Kim JS, Park YA, Lee DH, Park M, Yee J, et al. Transporter Genes and statin-induced Hepatotoxicity. Cardiovasc Drugs Ther 2025;39(4):801-810. [CrossRef][PubMed]
Cleophas MC, Joosten LA, Stamp LK, Dalbeth N, Woodward OM, Merriman TR. ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches. Pharmgenomics Pers Med 2017;10:129-42. [CrossRef][PubMed]
Cooper-DeHoff RM, Niemi M, Ramsey LB, Luzum JA, Tarkiainen EK, Straka RJ, et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and statin-associated musculoskeletal symptoms. Clin Pharmacol Ther 2022;111:1007–21. [CrossRef][PubMed]
de Keyser CE, Peters BJ, Becker ML, Visser LE, Uitterlinden AG, Klungel OH, et al. The SLCO1B1 c.521T>C polymorphism is associated with dose decrease or switching during statin therapy in the Rotterdam Study. Pharmacogenet Genomics 2014;24(1):43-51. [CrossRef][PubMed]
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(4):400-8. [CrossRef][PubMed]
Ferro CJ, Mark PB, Kanbay M, Sarafidis P, Heine GH, Rossignol P, et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol 2018;14(12):727-49. [CrossRef][PubMed]
Guan ZW, Wu KR, Li R, Yin Y, Li XL, Zhang SF, et al. Pharmacogenetics of statins treatment: Efficacy and safety. J Clin Pharm Ther 2019;44(6):858-67. [CrossRef][PubMed]
Hirota T, Fujita Y, Ieiri I. An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins. Expert Opin Drug Metab Toxicol 2020;16(9):809-22. [CrossRef][PubMed]
Ieiri I, Higuchi S, Sugiyama Y. Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol 2009;5(7):703-29. [CrossRef][PubMed]
Keskitalo JE, Zolk O, Fromm MF, Kurkinen KJ, Neuvonen PJ, Niemi M. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 2009;86(2):197-203. [CrossRef][PubMed]
Kim HS, Lee SH, Kim H, Lee SH, Cho JH, Lee H, et al. Statin-related aminotransferase elevation according to baseline aminotransferases level in real practice in Korea. J Clin Pharm Ther 2016;41(3):266-72. [CrossRef][PubMed]
Lee CK, Chen IC, Lin HJ, Lin CH, Chen YM. Association of the ABCG2 rs2231142 variant with the Framingham Cardiovascular Disease Risk score in the Taiwanese population. Heliyon 2024;10(18):e37839. [CrossRef][PubMed]
Lee HK, Hu M, Lui SSh, Ho CS, Wong CK, Tomlinson B. Effects of polymorphisms in ABCG2, SLCO1B1, SLC10A1 and CYP2C9/19 on plasma concentrations of rosuvastatin and lipid response in Chinese patients. Pharmacogenomics 2013;14(11):1283-94. [CrossRef][PubMed]
Lehtisalo M, Taskinen S, Tarkiainen EK, Neuvonen M, Viinamäki J, Paile-Hyvärinen M, et al. A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Br J Clin Pharmacol 2023;89(1):242-52. [CrossRef][PubMed]
Liu Y, Chen Y, Wei B, Li H, Peng Y, Luo Z. Impacts of ABCG2 loss of function variant (p. Gln141Lys, c.421 C > A, rs2231142) on lipid levels and statin efficiency: a systematic review and meta-analysis. BMC Cardiovasc Disord 2024;24(1):202. [CrossRef][PubMed]
Morisaki K, Robey RW, Ozvegy-Laczka C, Honjo Y, Polgar O, Steadman K, et al. Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol 2005;56(2):161-72. [CrossRef][PubMed]
Oesterle A, Liao JK. The Pleiotropic Effects of Statins - From Coronary Artery Disease and Stroke to Atrial Fibrillation and Ventricular Tachyarrhythmia. Curr Vasc Pharmacol 2019;17(3):222-32. [CrossRef][PubMed]
Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 2007;82(6):726-33. [CrossRef][PubMed]
Rodrigues AC, Hirata MH, Hirata RD. Impact of cholesterol on ABC and SLC transporters expression and function and its role in disposition variability to lipid-lowering drugs. Pharmacogenomics 2009;10(6):1007-16. [CrossRef][PubMed]
Romaine SP, Bailey KM, Hall AS, Balmforth AJ. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J 2010;10(1):1-11. [CrossRef][PubMed]
Sainz de Medrano Sainz JI, Brunet Serra M. Influence of pharmacogenetics on the diversity of response to statins associated with adverse drug reactions. Adv Lab Med 2023;4(4):341-52. [CrossRef][PubMed]
Silveira AMR, Duarte GHB, Fernandes AMAP, Garcia PHD, Vieira NR, Antonio MA et al. Serum Predose Metabolic Profiling for Prediction of Rosuvastatin Pharmacokinetic Parameters in Healthy Volunteers. Front Pharmacol 2021;12:752960. [CrossRef][PubMed]
Soko ND, Chimusa E, Masimirembwa C, Dandara C. An African-specific profile of pharmacogene variants for rosuvastatin plasma variability: limited role for SLCO1B1 c.521T>C and ABCG2 c.421A>C. Pharmacogenomics J 2019;19(3):240-48. [CrossRef][PubMed]
Sychev DA, Shuev GN, Chertovskih JV, Maksimova NR, Grachev AV, Syrkova OA. The frequency of SLCO1B1*5 polymorphism genotypes among Russian and Sakha (Yakutia) patients with hypercholesterolemia. Pharmgenomics Pers Med 2016;9:59-63. [CrossRef][PubMed]
Tachibana-Iimori R, Tabara Y, Kusuhara H, Kohara K, Kawamoto R, Nakura J, et al. Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metab Pharmacokinet 2004;19(5):375-80. [CrossRef][PubMed]
Tomlinson B, Hu M, Lee VW, Lui SS, Chu TT, Poon EW, et al. ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther 2010;87(5):558-62. [CrossRef][PubMed]
Vargas-Morales JM, Guevara-Cruz M, Aradillas-García C, G Noriega L, Tovar A, Alegría-Torres JA. Polymorphisms of the genes ABCG2, SLC22A12 and XDH and their relation with hyperuricemia and hypercholesterolemia in Mexican young adults. F1000Res 2021;10:217. [CrossRef][PubMed]
Verdoodt A, Honore PM, Jacobs R, De Waele E, Van Gorp V, De Regt J, et al. Do Statins Induce or Protect from Acute Kidney Injury and Chronic Kidney Disease: An Update Review in 2018. J Transl Int Med 2018;6(1):21-5. [CrossRef][PubMed]
Villani R, Navarese EP, Cavallone F, Kubica J, Bellanti F, Facciorusso A, et al. Risk of Statin-Induced Hypertransaminasemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Mayo Clin Proc Innov Qual Outcomes 2019;3(2):131-40. [CrossRef][PubMed]
Zakria M, Hussain A, Ahmad N, Ahmed N, Rauf MA, Siraj S. The lipid-lowering efficacy of rosuvastatin is associated with variations in SLCO1B1: a 12-month prospective cohort study. Eur Rev Med Pharmacol Sci 2023;27(10):4708-17. [CrossRef][PubMed]
Zhang D, Ding Y, Wang X, Xin W, Du W, Chen W, et al. Effects of ABCG2 and SLCO1B1 gene variants on inflammation markers in patients with hypercholesterolemia and diabetes mellitus treated with rosuvastatin. Eur J Clin Pharmacol 2020;76(7):939-46. [CrossRef][PubMed]
