Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review

Abstract

Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1.

Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia

“…14 Furthermore, a large systematic review of genetic factors that could influence statin-associated muscle symptoms showed that African Americans have different genetic variants of cytochrome P450 enzymes and influx transporter SLCO1B1 that may affect statin concentrations and subsequent statin-associated muscle symptoms. 15 In fact, in our study, lower BMI was associated with muscle symptoms only in non-African Americans but not African-Americans, and African Americans have lower percentage of the SLCO1B1 TC genotype compared to non-African Americans. Given a small sample size of our study, we may not be detecting independent increased risk of muscle symptoms in African Americans.…”

Ciprofloxacin and statin interaction: a cautionary tale of rhabdomyolysis

“…Another theory surrounds the role of the multiple drug protein-2 (a membrane transport protein from the ABC superfamily excreting toxins into bile), since simvastatin is a substrate of this transporter 15. Finally, there are several genetic factors that may also predispose one to statin-related toxicity16 or genetic mutations (eg, involving CYP2C8) which may be relevant in a statin–ciprofloxacin interaction 5…”

Performance of Exome Sequencing for Pharmacogenomics

“…In our datasets, COMT should not be relied upon as a PGx marker. In contrast, it should be noted that many of the well-known genes associated with drug response were adequately covered for genotype analysis: CYP2D6 (tamoxifen) [19,20], CYP2C19 (clopidogrel) [21,22], SLCO1B1 (statins) [23,24] (data not shown).…”