This DGI pertains to the interaction between the SLCO1B1 gene and simvastatin. Extensive literature and FDA warning labels indicate increased risk for myopathy in patients with a specific genetic differences on the SLCO1B1 gene.
INTERMEDIATE MYOPATHY RISK
Alternate therapy recommendations:
The SLCO1B1 gene encodes a liver-specific protein in the organic anion transporter family. The encoded protein is involved in the removal of drugs such as statins from the blood into the liver. Patients at Intermediate Risk for myopathy carry one copy of a variant in SLCO1B1 that results in a low-functioning SLCO1B1 protein. The gene product is coded by the *5 variant, which may also be expressed as the heterozygous ‘CT’ genoytpe. Switching therapy is recommended for patients at intermediate risk.
HIGH MYOPATHY RISK
The SLCO1B1 gene encodes a liver-specific protein in the organic anion transporter family. The encoded protein is involved in the removal of drugs such as statins from the blood into the liver. Patients at High Risk for myopathy carry two copies of a variant in SLCO1B1 that results in a low-functioning SLCO1B1 protein. The gene product is coded by the *5 variant, which may also be expressed as the homozygyous ‘CC’ genoytpe. Switching therapy is recommended for patients at high risk.
Genotyping for SCLO1B1 was performed within a high complexity, certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement act of 1988. This validated clinical Laboratory Developed Test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be >99%.
SEARCH Collaborative Group, Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R. N Engl J Med. 2008 Aug 21;359(8):789-99. Epub 2008 Jul 23.
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=4×10(-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.)
The SLCO1B1*5 genetic variant is associated with statin-induced side effects.
Voora D, Shah SH, Spasojevic I, Ali S, Reed CR, Salisbury BA, Ginsburg GS. J Am Coll Cardiol. 2009 Oct 20;54(17):1617-8.
OBJECTIVES: We sought to identify single nucleotide polymorphisms associated with mild statin-induced side effects.
BACKGROUND: Statin-induced side effects can interfere with therapy. Single nucleotide polymorphisms in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with creatine kinase (CK) elevation.
METHODS: The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a pharmacogenetics study of statin efficacy and safety. Subjects (n = 509) were randomized to atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg followed by 80 mg, 80 mg, and 40 mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK >3x upper limit of normal during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested 7 reduced function alleles for association with the CAE.
RESULTS: The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and 9 CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p < 0.01). SLCO1B1*5 was associated with CAE (percent with > or = 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p = 0.03) and those with CAE with no significant CK elevation (p < or = 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be greatest in those carriers assigned to simvastatin.
CONCLUSIONS: SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome-wide association study of statin myopathy with CK >3x normal to milder, statin-induced, muscle side effects.
Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin.
Brunham LR, Lansberg PJ, Zhang L, Miao F, Carter C, Hovingh GK, Visscher H, Jukema JW, Stalenhoef AF, Ross CJ, Carleton BC, Kastelein JJ, Hayden MR. Pharmacogenomics J. 2011 Jan 18. [Epub ahead of print]