Statin-Induced Myopathy: A Genetic Association

Statins can substantially reduce the risk for cardiovascular events but can also occasionally cause myopathy. High doses of statins increase the risk for myopathy, as does concomitant use of certain drugs, including amiodarone. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), a randomized comparison of 80-mg and 20-mg daily doses of simvastatin, provided an opportunity to investigate whether specific genetic variants are associated with this adverse effect. Of the 6031 patients in the high-dose group, 98 developed myopathy during 6 years of follow-up.

Investigators performed a genome-wide association study of 85 subjects with definite or incipient myopathy and 90 controls matched for sex, age, estimated glomerular filtration rate, and use or nonuse of amiodarone at baseline. In the analysis of discrete single nucleotide polymorphisms (SNPs), myopathy was strongly associated with the rs4363657 SNP located within SLCO1B1, which encodes an organic anion-transporting polypeptide that regulates the hepatic uptake of statins. The odds ratio for myopathy with this SNP was 4.3 (95% confidence interval, 2.5–7.2) per copy of the C allele and 17.4 (95% CI, 4.8–62.9) for CC homozygotes compared with TT homozygotes. Candidate genotyping and analysis within SLCO1B1 revealed a similar association with the rs4149056 SNP. The population prevalence of the rs4149056 C allele was 0.15, and the cumulative risk for myopathy in individuals taking 80 mg daily of simvastatin was 18.0% for CC homozygotes, 3.0% for the CT genotype, and 0.6% for the TT genotype. The findings were validated in 16,664 participants in the Heart Protection Study.