The SEARCH Collaborative Group (2008) SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 359: 789–799

Statin therapy has proven efficacy for reducing the incidence of major adverse clinical events, but when administered in high doses these agents can cause myopathy. A means to identify those at increased risk of statin-induced myopathy could improve these agents' safety profiles and enable individualized dosing. The SEARCH investigators performed a well-powered, genomewide association study and identified common single-nucleotide polymorphisms (SNPs) that are strongly associated with statin-related myopathy.

The original SEARCH trial randomly allocated 6,031 patients to receive 80 mg simvastatin, of whom 85 developed myopathy and were genotyped for this study. The only association between myopathy and a SNP to yield an uncorrected P value of <10−5 was that between myopathy and the rs4363657 variant, a noncoding SNP of SLCO1B1 (P = 0.001 with the Bonferroni correction). Of note, SLCO1B1 encodes OATP1B1, a protein that regulates uptake of statins into the liver. Of the additional SNPs within SLCO1B1 and flanking regions that were identified, only one—rs4149056—was both in nearly complete linkage disequilibrium with rs4363657 and nonsynonymous. Odds ratios for myopathy were 4.5 per copy of the C allele (95% CI 2.6–7.7) and 16.9 for CC homozygotes (95% CI 4.7–61.1), when compared with TT homozygotes (P = 2 × 10−9). Among the 90 control patients who also received high-dose simvastatin, the population prevalence of rs4149056 was 0.15. Importantly, the association between rs4149056 and myopathy was validated by data from the HPS (P = 0.004; relative risk per C allele copy 2.6, 95% CI 1.3–5.0).