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: ORGSI 2.42[95%CI:1.29, 4.31], p=0.003; statin-related myopathy ORSRM 2.51[95%CI:1.28, 4.53],p=0.004; statin-related suspected rhabdomyolysis: ORSRSR 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 (ORVal174Ala 1.99 [95%CI:1.01, 3.95],p=0.048; ORrisk-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: HRVal174Ala 2.49 [95%CI:1.09, 5.68],p=0.03; HRrisk-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.
- genetic and genomic medicine