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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Vydáno v:	Pharmacogenetics and genomics Ročník 21; číslo 5; s. 280
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.05.2011
Témata:	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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1744-6880 1744-6880
DOI:	10.1097/FPC.0b013e328343dd7d