SLCO1B1 gene and statin myopathy (intolerance)

Genetic variation in SLCO1B1 has been described:

• the two most common functional variants in SLCO1B1 are rs4149056 and rs2306283
  • the C allele at rs4149056 (referred to as the *5 variant) causes a V174A substitution in the hepatic transporter protein OATP1B1 and is a risk factor for statin-induced side effects and premature drug discontinuation (1,2,3)
    • the *5 variant interferes with localization of the hepatic drug transporter to the plasma membrane, resulting in elevated systemic concentration of statins
    • the effect of the *5 variant on statin clearance appears to be statin-specific, where simvastatin and atorvastatin are most affected, followed by fluvastatin, pravastatin and rosuvastatin
    • risk of myopathy conferred by *5 mirrors this pharmacokinetic data, with the greatest effects on simvastatin and atorvastatin and the least on pravastatin and rosuvastatin
    • by interfering with statin transport into the hepatocyte, the *5 variant is associated with mild reductions in LDL-c lowering (1-3%) in short-term statin exposure studies (=1 year)
    • carriers of the SLCO1B1*5 allele (Val174Ala, rs4149056) are at 2-fold relative risk of mild statin induced side effects, the majority of which had normal CK levels. These results could have potential implications for clinical practice because the vast majority of patients who are intolerant of statin have mild symptoms without CK elevations (2)
      
      
  • in contrast to the *5 variant, which reduces OATP1B1 function, the G allele at rs2306283 (referred to as the *1B variant) causes an N130D substitution that may increase OATP1B1 function
    • as a consequence, the G allele reduces systemic statin concentrations as well as the risk for statin-induced side effects but does not result in differences in LDL-c lowering
      
      
• in a large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men (4)

Reference:

• Link E, Parish S, et al. SLCO1B1 variants and statin-induced myopathy - a genomewide study. N Engl J Med. 2008;359(8):789-799.
• Voora D, Shah SH, Spasojevic I, et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009;54(17):1609-1616.
• Donnelly LA, Doney AS, Tavendale R, et al. Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study. Clin Pharmacol Ther. 2011;89(2):210-216.
• Turkmen D et al. Statin treatment effectiveness and the SLCO1B1 *5 reduced function genotype: Long-term outcomes in women and men. BJCP January 2022; https://doi.org/10.1111/bcp.15245