Investigation of the association between genetics, drug exposure and statin-induced muscle toxicity

Abstract

Statins are generally well-tolerated, although statin-related myotoxicity (SRM) has been reported in a considerable number of patients. The risk factors underlying SRM have yet to be fully characterised. This study aimed to further elucidate the risk factors that increase the likelihood of SRM using data generated from cellular and clinical settings. The data from the cellular studies would provide information regarding candidate single nucleotide polymorphisms (SNPs) which could be tested in the clinical setting. In the cellular studies, three model cell lines were used; human proximal tubule (HK-2), rat skeletal muscle (L6) and human muscle cells. Lipophilic statins, simvastatin and atorvastatin, inhibited monocarboxylate transporter 1 (MCT1)-mediated DL-lactate uptake at the same magnitude as phloretin, a well-known MCT1 inhibitor. No significant lactate uptake inhibition was observed with up to 1 mM of hydrophilic statins (pravastatin and rosuvastatin). The magnitudes of inhibition of multidrug resistance-associated protein (MRP)-mediated CMFDA efflux and MDR1-mediated Hoeschst 33342 efflux by the lipophilic statins were lower than that caused by MK571 and cyclosporine A, which are typical inhibitors of MRP and MDR1, respectively. Both hydrophilic statins showed no significant effect on MRPs and MDR1 functions. In the clinical setting, a case-control study (116 cases and 314 controls) of unrelated dyslipidaemic patients was performed to determine the association between 12 SNPs from nine focus genes [i.e., SLCO1B1, ABCC2, ABCG2, CYP3A4 (*22 allele), COQ2, GATM, GPx, SLC16A1, SLC16A3] and SRM. Of the 12 SNPs genotyped, only SNP in SLCO1B1 (rs4149056) appeared to be the most important genetic predictor of SRM (P = 0.059, P = 0.047 in univariate and multivariate analysis, respectively), thus confirming previous findings. The association between rs4149056 and SRM was demonstrated to be independent to the type of administered statins and was likely to be influenced by the patient gender. Further patient recruitment is ongoing to increase study power and to confirm the assumption of the abovementioned association.