The SLCO1B1*5Genetic Variant Is Associated With Statin-Induced Side Effects

Abstract

Objectives Identify SNPs associated with mild statin-induced side effects. Background Statin-induced side effects can interfere with therapy. SNPs in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with CK elevation. Methods The STRENGTH study was a pharmacogenetics study of statin efficacy and safety. Subjects (n=509) were randomized to atorvastatin 10mg, simvastatin 20mg, or pravastatin 10mg followed by 80mg, 80mg, and 40mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK>3× baseline during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested seven reduced function alleles for association with the CAE. Results The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and nine CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p<0.01). SLCO1B1*5 was associated with CAE (percent with ≥ 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p=0.03) and those with CAE with no significant CK elevation (p≤ 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be highest in those carriers assigned to simvastatin. Conclusions SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome wide association study of statin myopathy with CK > 3 times normal to milder, statin-induced, muscle side effects.

Association between <i>SLCO1B1 521 T</i>＞<i>C</i> and <i>388 A</i>＞<i>G </i>Polymorphisms and Statins Effectiveness: A Meta-Analysis

“…Specially, Shabana et al maintained that the polymorphism showed gender-related effects on TG change following the atorvastatin treatment 31) . Although the benefits of statins in the prevention of coronary heart disease has been demonstrated by primary and secondary prevention trials [2][3][4][5][6][7][8][9][10][11][12] , there is inter-individual variability among the statin therapeutic response and some studies [32][33][34][35][36][37] recognized that genetic polymorphisms may influence the drug disposition, side effects and statin effectiveness. Due to the inconsistency in the existing literature and in order to overcome the limitation of individual studies, we performed this meta-analysis to provide a more precise and comprehensive estimation of the association between the SLCO1B1 521 T C and 388 A G polymorphisms and statin effectiveness.…”

Statin-related myotoxicity

“…35 Genes related to statin metabolism and action have been studied, including those related to liver uptake, bile excretion, and liver metabolism of statins, as well as CK activity and hereditary metabolic myopathies. 22 Although the mechanisms and genes involved are not extensively known, the following are illustrative examples: 1,22,36,37 • SLCO1B1 ---this gene encodes the organic anion transporting polypeptide 1B1 (OATP1B1), which is responsible for liver uptake of most statins. Common variants of SLCO1B1 influence the risk of muscle toxicity in patients taking simvastatin.…”

The Pharmacogenetics of Cardiovascular Drugs / FARMAKOGENETIKA KARDIOVASKULARNIH LEKOVA

“…The c388A-c521T haplotype is known as *1A (reference haplotype), c388G-c521T as *1B, c388A-c521C as *5 and c388G-c521C as *15. Carriers of *5 are at 4-to 5-fold increased risk of severe, creatine kinase-positive simvastatin-induced myopathy and 2-to 3-fold increased risk of creatine kinase-negative myopathy (46,48).…”