The SLCO1B1*5 Genetic Variant Is Associated With Statin-Induced Side Effects
Received 13 January 2009; received in revised form 9 April 2009; accepted 13 April 2009.
Refers to article:
The Pharmacogenetics of Statin Therapy: When the Body Aches, the Mind Will Follow⁎
Joseph S. Rossi, Howard L. McLeod
Journal of the American College of Cardiology
20 October 2009 (Vol. 54, Issue 17, Pages 1617-1618) Full Text |
Full-Text PDF (111 KB)
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 >3× 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 >3× normal to milder, statin-induced, muscle side effects.
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
This work was supported by institutional funds from the Duke Institute for Genome Sciences & Policy. Dr. Voora was supported by an NIH T32 training grant (T32HL007101). Dr. Shah received unrestricted research funding from Medtronic, Inc. This trial was conducted by Genaissance Pharmaceuticals, which is now a part of Clinical Data, Inc., and all analyses were performed by investigators at Duke University. Two authors (Drs. Reed and Salisbury) are employees and shareholders of Clinical Data, Inc. Paul Thompson, MD, served as Guest Editor for this article.
ABSTRACT