Variants of SLCO1B1 Associated with Statin-Induced Myopathy
A genomewide screen of patients with myopathy who were taking high-dose simvastatin showed a strong association between myopathy and variants of SLCO1B1, which encodes an organic anion–transporting polypeptide.
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The SEARCH Collaborative Group. SLCO1B1 Variants and Statin-Induced Myopathy  A Genomewide Study. N Eng J Med 2008 Jul 23
DOI: 10.1056/NEJMoa0801936
http://content.nejm.org/cgi/content/abstract/NEJMoa0801936v1 http://content.nejm.org/cgi/content/full/NEJMoa0801936
http://content.nejm.org/cgi/reprint/NEJMoa0801936v1.pdf
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N Engl J Med. 2008 Jul 23. [Epub ahead of print]
SLCO1B1 Variants and Statin-Induced Myopathy -- A Genomewide Study.
The SEARCH Collaborative Group.
The investigators and institutions participating in the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) are listed in the Appendix and in the Supplementary Appendix, available with the full text of this article at www.nejm.org. This article (10.1056/NEJMoa0801936) was published at www.nejm.org on July 23, 2008. It will appear in the August 21 issue of the Journal.
BACKGROUND: Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. METHODS: We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. RESULTS: The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. CONCLUSIONS: We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.) Copyright 2008 Massachusetts Medical Society.
PMID: 18650507