Cerivastatin, genetic variants, and the risk of rhabdomyolysis

The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associ...

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Published in:Pharmacogenetics and genomics Vol. 21; no. 5; p. 280
Main Authors: Marciante, Kristin D, Durda, Jon P, Heckbert, Susan R, Lumley, Thomas, Rice, Ken, McKnight, Barbara, Totah, Rheem A, Tamraz, Bani, Kroetz, Deanna L, Fukushima, Hisayo, Kaspera, Rüdiger, Bis, Joshua C, Glazer, Nicole L, Li, Guo, Austin, Thomas R, Taylor, Kent D, Rotter, Jerome I, Jaquish, Cashell E, Kwok, Pui-Yan, Tracy, Russell P, Psaty, Bruce M
Format: Journal Article
Language:English
Published: United States 01.05.2011
Subjects:
Adult
Aged
Aged, 80 and over
Aryl Hydrocarbon Hydroxylases - genetics
Case-Control Studies
Cytochrome P-450 CYP2C8
Female
Genetic Variation
Genome-Wide Association Study
Glucuronosyltransferase - genetics
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use
Liver-Specific Organic Anion Transporter 1
Male
Middle Aged
Organic Anion Transporters - genetics
Polymorphism, Single Nucleotide
Pyridines - adverse effects
Pyridines - therapeutic use
Rhabdomyolysis - chemically induced
Rhabdomyolysis - genetics
Risk
Ryanodine Receptor Calcium Release Channel - genetics
ISSN:1744-6880, 1744-6880
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Summary:The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63). We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.
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ISSN:1744-6880
1744-6880
DOI:10.1097/FPC.0b013e328343dd7d