Common and rare variants in SLCO1B1 are associated with statin intolerance

Background and Aims The efficacy of statin therapy is hindered by adverse drug reactions, most frequently musculoskeletal symptoms. Variants in SLCO1B1 , which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentration of the drug and its metabolites. While pharmacogenetic testing of the loss-of-function Val174Ala (rs4149056T>C) is recommended to reduce risk of statin intolerance, current guidelines acknowledge the potential role of gain-of-function variants. This study tests the hypothesis that accounting for gain-of-function variants in SLCO1B1 , in addition to Val174Ala, will provide more reliable estimates of statin intolerance. Methods and Results High-risk haplotypes were derived from Val174Ala and three common gain-of-function SLCO1B1 variants and compared to low-risk haplotypes. In statin users from Tayside Scotland, UK, those with high-risk haplotypes had increased odds across three phenotypes of statin intolerance (general statin intolerance: OR GSI 2.42[95%CI:1.29, 4.31], p=0.003; statin-related myopathy OR SRM 2.51[95%CI:1.28, 4.53],p=0.004; statin-related suspected rhabdomyolysis: OR SRSR 2.85[95%CI:1.03, 6.65],p=0.02). In contrast, using the Val174Ala genotype alone produced weaker results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (OR Val174Ala 1.99 [95%CI:1.01, 3.95],p=0.048; OR risk-haplotypes 1.76 [95%CI:1.16, 2.69],p=0.008). For those requiring high-dose statin therapy, high-risk haplotypes were more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared to Val174Ala (general statin intolerance: HR Val174Ala 2.49 [95%CI:1.09, 5.68],p=0.03; HR risk-haplotypes 2.44 [95%CI:1.46, 4.08],p<0.001). Exome-sequenced rare variants were found to be associated with the risk of intolerance (p=0.02). Conclusions We demonstrate that accounting for gain-of-function variants in SLCO1B1 , in addition to Val174Ala, provides more reliable estimates of statin intolerance.