Association of SLCO1B1 and ABCB1 Genetic Variants with Atorvastatin-induced Myopathy in Patients with Acute Ischemic Stroke

Author(s): Limin Zhang, Hong Lv, Qian Zhang, Dongzhi Wang, Xixiong Kang, Guojun Zhang*, Xingang Li*.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 14 , 2019

Abstract:

Background: Certain patients experience muscle-related adverse effects after taking atorvastatin. Genetic factors play an important role in the occurrence of statin-induced myopathy.

Aim: We aimed to identify genetic variants associated with statin-induced myotoxicity.

Methods: We prospectively enrolled 1,102 acute ischemic stroke patients who underwent atorvastatin treatment for the first time after admission. Patients were separated into case and control groups after a follow-up of 3 months. We used a biochemical definition of myopathy consisting of serum creatine kinase values more than ten times the upper limit of normal for the reference laboratory (150 U/L). Fifty single nucleotide polymorphisms (SNPs) from seven genes of ABCB1, CoQ2, HTR3B, RYR2, CYP3A5, HTR7 and SLCO1B1 were selected and genotyped. The effects of genetic polymorphisms on myopathy were observed.

Results: 61 cases and 110 controls were recruited in the study. Compared with the controls, the cases had a significant higher mutant frequency of the allele A (ABCB1, rs2373588) (OR = 2.01, 95%CI = 1.10-3.67, P = 0.001) and a significant lower mutant frequency of the allele A (SLCO1B1, rs976754) (OR = 1.85, 95%CI = 1.12-3.03, P = 0.042). Genotypes or alleles of the other SNPs had no significant difference between the two groups (P > 0.05).

Conclusion: Our findings reveal that SLCO1B1 and ABCB1 genetic variants are associated with statin-induced myopathy. These are valuable biomarkers for the evaluation of atorvastatin safety.

Keywords: SLCO1B1, ABCB1, statin-induced myopathy, single nucleotide polymorphism, biomarkers, atorvastatin, acute ischemic stroke.

[1]
Liu JE, Liu XY, Chen S, et al. SLCO1B1 521T > C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: A nested case-control study. Eur J Clin Pharmacol 2017; 73(11): 1409-16. [http://dx.doi.org/10.1007/s00228-017-2318-z]. [PMID: 28812116].
[2]
Hermann M, Bogsrud MP, Molden E, et al. Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy. Clin Pharmacol Ther 2006; 79(6): 532-9. [http://dx.doi.org/10.1016/j.clpt.2006.02.014]. [PMID: 16765141].
[3]
Parker BA, Thompson PD. Effect of statins on skeletal muscle: Exercise, myopathy, and muscle outcomes. Exerc Sport Sci Rev 2012; 40(4): 188-94. [http://dx.doi.org/10.1097/JES.0b013e31826c169e]. [PMID: 23000957].
[4]
Vladutiu GD, Isackson PJ, Kaufman K, et al. Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. Mol Genet Metab 2011; 104(1-2): 167-73. [http://dx.doi.org/10.1016/j.ymgme.2011.07.001]. [PMID: 21795085].
[5]
Baker SK, Vladutiu GD, Peltier WL, Isackson PJ, Tarnopolsky MA. Metabolic myopathies discovered during investigations of statin myopathy. Can J Neurol Sci 2008; 35(1): 94-7. [http://dx.doi.org/10.1017/S0317167100007630]. [PMID: 18380285].
[6]
Ulvestad M, Skottheim IB, Jakobsen GS, et al. Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects. Clin Pharmacol Ther 2013; 93(3): 275-82. [http://dx.doi.org/10.1038/clpt.2012.261]. [PMID: 23361102].
[7]
Hou Q, Li S, Li L, Li Y, Sun X, Tian H. Association Between SLCO1B1 Gene T521C Polymorphism and Statin-Related Myopathy Risk: A Meta-Analysis of Case-Control. Studies Medicine 2015; 94(37)e1268 [http://dx.doi.org/10.1097/MD.0000000000001268]. [PMID: 26376374].
[8]
Danik JS, Chasman DI, MacFadyen JG, Nyberg F, Barratt BJ, Ridker PM. Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy. Am Heart J 2013; 165(6): 1008-14. [http://dx.doi.org/10.1016/j.ahj.2013.01.025]. [PMID: 23708174].
[9]
Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med 2008; 359(8): 789-99. [http://dx.doi.org/10.1056/NEJMoa0801936]. [PMID: 18650507].
[10]
Brunham LR, Lansberg PJ, Zhang L, et al. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics J 2012; 12(3): 233-7. [http://dx.doi.org/10.1038/tpj.2010.92]. [PMID: 21243006].
[11]
Oh J, Ban MR, Miskie BA, et al. Genetic determinants of statin intolerance. Lipids Health Dis 2007; 6(7) [http://dx.doi.org/10.1186/1476-511X-6-7].
[12]
Ruaño G, Thompson PD, Windemuth A, et al. Physiogenomic association of statin-related myalgia to serotonin receptors. Muscle Nerve 2007; 36(3): 329-35. [http://dx.doi.org/10.1002/mus.20871]. [PMID: 17600820].
[13]
Hubacek JA, Adamkova V, Hruba P, Ceska R, Vrablik M. Association between polymorphism within the RYR2 receptor and development of statin-associated myalgia/myopathy in the Czech population. Eur J Intern Med 2015; 26(5): 367-8. [http://dx.doi.org/10.1016/j.ejim.2015.02.019]. [PMID: 25753936].
[14]
Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J 2014; 168(1): 6-15. [http://dx.doi.org/10.1016/j.ahj.2014.03.019]. [PMID: 24952854].
[15]
Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): An internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012; 6(3): 208-15. [http://dx.doi.org/10.1016/j.jacl.2012.03.003]. [PMID: 22658145].
[16]
Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: Impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36(17): 1012-22. [http://dx.doi.org/10.1093/eurheartj/ehv043]. [PMID: 25694464].
[17]
Thompson PD, Panza G, Zaleski A, Taylor B. Statin-Associated Side Effects. J Am Coll Cardiol 2016; 67(20): 2395-410. [http://dx.doi.org/10.1016/j.jacc.2016.02.071]. [PMID: 27199064].
[18]
Gong IY, Kim RB. Impact of genetic variation in OATP transporters to drug disposition and response. Drug Metab Pharmacokinet 2013; 28(1): 4-18. [http://dx.doi.org/10.2133/dmpk.DMPK-12-RV-099]. [PMID: 23047721].
[19]
Santos PC, Gagliardi AC, Miname MH, et al. SLCO1B1 haplotypes are not associated with atorvastatin-induced myalgia in Brazilian patients with familial hypercholesterolemia. Eur J Clin Pharmacol 2012; 68(3): 273-9. [http://dx.doi.org/10.1007/s00228-011-1125-1]. [PMID: 21928084].
[20]
Canestaro WJ, Brooks DG, Chaplin D, et al. Statin pharmacogenomics: Opportunities to improve patient outcomes and healthcare costs with genetic testing. J Pers Med 2012; 2(4): 158-74. [http://dx.doi.org/10.3390/jpm2040158]. [PMID: 25562358].
[21]
Hoenig MR, Walker PJ, Gurnsey C, Beadle K, Johnson L. The C3435T polymorphism in ABCB1 influences atorvastatin efficacy and muscle symptoms in a high-risk vascular cohort. J Clin Lipidol 2011; 5(2): 91-6. [http://dx.doi.org/10.1016/j.jacl.2011.01.001]. [PMID: 21392722].
[22]
Prado Y, Zambrano T, Salazar LA. Transporter genes ABCG2 rs2231142 and ABCB1 rs1128503 polymorphisms and atorvastatin response in Chilean subjects. J Clin Pharm Ther 2018; 43(1): 87-91. [http://dx.doi.org/10.1111/jcpt.12607]. [PMID: 28833323].
[23]
Choi HY, Bae KS, Cho SH, 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. [http://dx.doi.org/10.1097/FPC.0000000000000176]. [PMID: 26367500].
[24]
Wu LX, Zhao HB, Wen CJ, et al. Combined Influence of Genetic Polymorphism and DNA Methylation on ABCB1 Expression and Function in Healthy Chinese Males. Eur J Drug Metab Pharmacokinet 2017; 42(4): 627-34. [http://dx.doi.org/10.1007/s13318-016-0376-8]. [PMID: 27683186].
[25]
Wu LX, Wen CJ, Li Y, et al. Interindividual epigenetic variation in ABCB1 promoter and its relationship with ABCB1 expression and function in healthy Chinese subjects. Br J Clin Pharmacol 2015; 80(5): 1109-21. [http://dx.doi.org/10.1111/bcp.12675]. [PMID: 25940551].
[26]
Li XQ, Ma N, Li XG, et al. Association of PON1, P2Y12 and COX1 with Recurrent Ischemic Events in Patients with Extracranial or Intracranial Stenting. PLoS One 2016; 11(2)e0148891 [http://dx.doi.org/10.1371/journal.pone.0148891]. [PMID: 26870959].
[27]
El-Salem K, Ababneh B, Rudnicki S, et al. Prevalence and risk factors of muscle complications secondary to statins. Muscle Nerve 2011; 44(6): 877-81. [http://dx.doi.org/10.1002/mus.22205]. [PMID: 22102457].


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Article Details

VOLUME: 25
ISSUE: 14
Year: 2019
Page: [1663 - 1670]
Pages: 8
DOI: 10.2174/1381612825666190705204614
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