03692nas a2200637 4500008004100000022001400041245006800055210006500123260001300188300001000201490000700211520184500218653001002063653000902073653002202082653003402104653002502138653002802163653001102191653002202202653003402224653002802258653001102286653005102297653000902348653001602357653003102373653003602404653001402440653001902454653000902473653004702482653006302529100002602592700001802618700002302636700001902659700001402678700002202692700002002714700001702734700002202751700002202773700002202795700001902817700002202836700001202858700002202870700002002892700002202912700002402934700001802958700002202976700002002998856003603018 2011 eng d a1744-688000aCerivastatin, genetic variants, and the risk of rhabdomyolysis.0 aCerivastatin genetic variants and the risk of rhabdomyolysis c2011 May a280-80 v213 a
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.
10aAdult10aAged10aAged, 80 and over10aAryl Hydrocarbon Hydroxylases10aCase-Control Studies10aCytochrome P-450 CYP2C810aFemale10aGenetic Variation10aGenome-Wide Association Study10aGlucuronosyltransferase10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aOrganic Anion Transporters10aPolymorphism, Single Nucleotide10aPyridines10aRhabdomyolysis10aRisk10aRyanodine Receptor Calcium Release Channel10aSolute Carrier Organic Anion Transporter Family Member 1b11 aMarciante, Kristin, D1 aDurda, Jon, P1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Ken1 aMcKnight, Barbara1 aTotah, Rheem, A1 aTamraz, Bani1 aKroetz, Deanna, L1 aFukushima, Hisayo1 aKaspera, RĂ¼diger1 aBis, Joshua, C1 aGlazer, Nicole, L1 aLi, Guo1 aAustin, Thomas, R1 aTaylor, Kent, D1 aRotter, Jerome, I1 aJaquish, Cashell, E1 aKwok, Pui-Yan1 aTracy, Russell, P1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/1275