An additional copy of the minor allele of SLCO1B1 rs4149056 was associated with an increased risk of cerivastatin-associated rhabdomyolysis (OR 1.89; 95% CI 1.40-2.56).
Case-Control (n=917)
Yes
Are genetic variants associated with the risk of cerivastatin-associated rhabdomyolysis in statin users?
Genetic variants in SLCO1B1 and RYR2 are modest risk factors for cerivastatin-associated rhabdomyolysis, but disabling variants in candidate genes do not fully explain the bimodal response.
Odds Ratio: 1.89 (95% CI 1.4–2.56)
p-value: p=0.002
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Marciante et al. (Tue,) conducted a case-control in Cerivastatin-associated rhabdomyolysis (n=917). SLCO1B1 rs4149056 minor allele vs. Reference allele was evaluated on Risk of rhabdomyolysis (OR 1.89, 95% CI 1.40-2.56, p=0.002). An additional copy of the minor allele of SLCO1B1 rs4149056 was associated with an increased risk of cerivastatin-associated rhabdomyolysis (OR 1.89; 95% CI 1.40-2.56).
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