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Cerivastatin, genetic variants, and the risk of rhabdomyolysis.
Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
| Title | Cerivastatin, genetic variants, and the risk of rhabdomyolysis. |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Marciante, KD, Durda, JP, Heckbert, SR, Lumley, T, Rice, K, McKnight, B, Totah, RA, Tamraz, B, Kroetz, DL, Fukushima, H, Kaspera, R, Bis, JC, Glazer, NL, Li, G, Austin, TR, Taylor, KD, Rotter, JI, Jaquish, CE, Kwok, P-Y, Tracy, RP, Psaty, BM |
| Journal | Pharmacogenet Genomics |
| Volume | 21 |
| Issue | 5 |
| Pagination | 280-8 |
| Date Published | 2011 May |
| ISSN | 1744-6880 |
| Keywords | Adult, Aged, Aged, 80 and over, Aryl Hydrocarbon Hydroxylases, Case-Control Studies, Cytochrome P-450 CYP2C8, Female, Genetic Variation, Genome-Wide Association Study, Glucuronosyltransferase, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Organic Anion Transporters, Polymorphism, Single Nucleotide, Pyridines, Rhabdomyolysis, Risk, Ryanodine Receptor Calcium Release Channel, Solute Carrier Organic Anion Transporter Family Member 1b1 |
| Abstract | <p><b>OBJECTIVE: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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).</p><p><b>CONCLUSION: </b>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.</p> |
| DOI | 10.1097/FPC.0b013e328343dd7d |
| Alternate Journal | Pharmacogenet. Genomics |
| PubMed ID | 21386754 |
| PubMed Central ID | PMC3076530 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States N01 HC085086 / HC / NHLBI NIH HHS / United States HL068639 / HL / NHLBI NIH HHS / United States N01-HC-85085 / HC / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States N01 HC075150 / HC / NHLBI NIH HHS / United States HL085251 / HL / NHLBI NIH HHS / United States N01-HC-85081 / HC / NHLBI NIH HHS / United States R01 HL068986 / HL / NHLBI NIH HHS / United States HL73410 / HL / NHLBI NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States R01 HL085251 / HL / NHLBI NIH HHS / United States P30 DK063491-06 / DK / NIDDK NIH HHS / United States R01 HL068639 / HL / NHLBI NIH HHS / United States R01 HL078888 / HL / NHLBI NIH HHS / United States R01 HL087652-01 / HL / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States R01 HL078888-01A1 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States R01 HL074745 / HL / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States HL068986 / HL / NHLBI NIH HHS / United States R01 HL085251-01A1 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States HL074745 / HL / NHLBI NIH HHS / United States N01-HC-85082 / HC / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States GM61390 / GM / NIGMS NIH HHS / United States N01 HC055222 / HC / NHLBI NIH HHS / United States N01-HC45133 / HC / NHLBI NIH HHS / United States N01-HC-55222 / HC / NHLBI NIH HHS / United States U01 GM061390 / GM / NIGMS NIH HHS / United States N01-HC-85083 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-85080 / HC / NHLBI NIH HHS / United States R01 HL080295 / HL / NHLBI NIH HHS / United States U19 GM061390 / GM / NIGMS NIH HHS / United States HL078888 / HL / NHLBI NIH HHS / United States R01 HL074745-01 / HL / NHLBI NIH HHS / United States M01 RR000425 / RR / NCRR NIH HHS / United States R01 HL043201-09A1 / HL / NHLBI NIH HHS / United States U01 GM061390-01 / GM / NIGMS NIH HHS / United States R01 HL068986-01A1 / HL / NHLBI NIH HHS / United States R01HL087652 / HL / NHLBI NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States R01 HL043201 / HL / NHLBI NIH HHS / United States HL43201 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States R01 HL080295-05 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01 HC085079 / HC / NHLBI NIH HHS / United States R01 HL073410-01A1 / HL / NHLBI NIH HHS / United States R01 HL073410 / HL / NHLBI NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States N01-HC-85084 / HC / NHLBI NIH HHS / United States R01 HL068639-01 / HL / NHLBI NIH HHS / United States M01 RR000425-30S1 / RR / NCRR NIH HHS / United States |