The SLCO1B1*5 Genetic Variant Is Associated With Statin-Induced Side Effects

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:54

Article

Voora, Deepak^1,3  Shah, Svati H.^1,2,3  Spasojevic, Ivan³  Ali, Shazia⁴  Reed, Carol R.⁵  Salisbury, Benjamin A.⁵  Ginsburg, Geoffrey S.^1,3,4 

[1] Duke Univ, Med Ctr, Div Cardiovasc Med, Durham, NC 27708 USA

[2] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27708 USA

[3] Duke Univ, Med Ctr, Dept Med, Durham, NC 27708 USA

[4] Duke Univ, Med Ctr, Inst Genome Sci & Policy, Durham, NC 27708 USA

[5] PGxHealth LLC, New Haven, CT USA

关键词: hydroxymethylglutaryl-CoA reductase inhibitors;    pharmacogenetics;    single nucleotide polymorphisms;    adverse events;    clinical trial;    myopathy;   

DOI  :  10.1016/j.jacc.2009.04.053

来源: Elsevier

【 摘 要 】

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 >= 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p = 0.03) and those with CAE with no significant CK elevation (p <= 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. (J Am Coll Cardiol 2009;54:1609-16) (C) 2009 by the American College of Cardiology Foundation

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