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CLINICAL RESEARCH: GENETICS AND STATIN EFFECTS

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

Deepak Voora, MD^_*,, Svati H. Shah, MD, MHS^_*,,, Ivan Spasojevic, PhD, Shazia Ali, PharmD, Carol R. Reed, MD^¶, Benjamin A. Salisbury, PhD^¶ and Geoffrey S. Ginsburg, MD, PhD^_*,,,_*

^_* Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina
Department of Medicine, Duke University Medical Center, Durham, North Carolina
Institute for Genome Sciences & Policy, Duke University Medical Center, Durham, North Carolina
^¶ PGxHealth, LLC, New Haven, Connecticut

Manuscript received January 13, 2009; revised manuscript received April 9, 2009, accepted April 13, 2009.

^_* Reprint requests and correspondence: Dr. Geoffrey S. Ginsburg, Institute for Genome Sciences & Policy, Center for Genomic Medicine, 2117 CIEMAS, 101 Science Drive, Duke University, DUMC Box 3382, Durham, North Carolina 27708 (Email: geoffrey.ginsburg{at}duke.edu).

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.

Key Words: hydroxymethylglutaryl-CoA reductase inhibitors • pharmacogenetics • single nucleotide polymorphisms • adverse events • clinical trial • myopathy

Abbreviations and Acronyms   AE = adverse event   CAE = composite adverse event   CK = creatine kinase   FDR = false discovery rate   LDL = low-density lipoprotein   MAF = minor allele frequencies   SNP = single nucleotide polymorphism

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