Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin

Abstract

Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

“…Similarly, Fu et al [31] reported no significant effect on atorvastatin efficacy in a Chinese population. In agreement with this are findings showing that genetic variants of OATP1B1 are not predictive for atorvastatin-associated myopathic side effects [15]. It should be noted at this point that in healthy volunteers, the OATP1B1 polymorphisms exerted a more pronounced effect on pharmacokinetic parameters of the atorvastatin acid levels compared with the less lipophilic rosuvastatin [32].…”

“…In particular, the frequent single nucleotide polymorphism (SNP) SLCO1B1 c.521C results in significant changes in pharmacokinetics (increased area under the curve) of several statins (pravastatin, atorvastatin, rosuvastatin and simvastatin) in healthy volunteers (summarized in the study of Niemi et al [13]). The assumption that OATP1B transporters are important in pharmacokinetics of statins is indirectly supported by findings showing that the frequently occurring functionimpairing allele SLCO1B1 c.521C is most predictive for extrahepatic adverse events (myopathy, rhabdomyolysis) of simvastatin therapy [14,15]. In detail, Link and colleagues had identified the noncoding rs4363657 polymorphism after performing a Genome-wide association scan in patients experiencing simvastatin-induced myopathy.…”

State-of-the-Art Technologies to Interrogate Genetic/Genomic Components of Drug Response

“…The association was replicated in patients on 40 mg of simvastatin and has subsequently also been replicated by other investigators [25]. Although this association seems to be important for simvastatin-induced myopathy, whether it is also important for the other statins still requires further study [26]. As with GWAS in complex diseases, a finding that might not show clinical value might still be of use in identifying the mechanism(s) of action of the drug [27 • , 28 • , 29 • ].…”

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“…68 It was statemented that plasma statin concentration liable to be higher in people with the above polymorphism, in consequence predisposing them to adverse effects. 67,69 On the other hand, modern studies have shown that this polymorphism might be largely associated with simvastatininduced myopathy. 70 It was identified by SEARCH collaborative group that rs4149056 polymorphism of SLCO1B1 (521C variant) was associated with a 4.5 fold increased risk of myopathy in heterozygotes and 17 fold higher risk in homozygotes when co administered with simvastatin 80 mg daily.…”