Abstract
Statins, a class of lipid-lowering medications, have been a keystone treatment in cardiovascular health. However, adverse effects associated with statin use impact patient adherence, leading to statin discontinuation. Statin-induced myotoxicity (SIM) is one of the most common adverse effects, prevalent across all ages, genders, and ethnicities. Although certain demographic cohorts carry a higher risk, the impaired quality of life attributed to SIM is significant. The pathogenesis of SIM remains to be fully elucidated, but it is clear that SIM is multifactorial. These factors include drug–drug interactions, renal or liver dysfunction, and genetics. Genetic-inferred risk for SIM was first reported by a landmark genome-wide association study, which reported a higher risk of SIM with a polymorphism in the SLCO1B1 gene. Since then, research associating genetic factors with SIM has expanded widely and has become one of the foci in the field of pharmacogenomics. This review provides an update on the genetic risk factors associated with SIM.
Highlights
Hydroxymethylglutaryl-coenzyme A reductase (HMG-CR) inhibitors, commonly known as statins, are indicated for hypercholesterolemia and atherosclerotic cardiovascular diseases (Grundy et al, 2019; Bartlomiejczyk et al, 2019)
Studies investigating the effect of the 1249G > A single-nucleotide polymorphisms (SNPs) on the PK profile of statins reported no association between the variant allele and plasma concentration or area under the concentration–time curve (AUC) of rosuvastatin (DeGorter et al, 2013), atorvastatin (DeGorter et al, 2013), pravastatin (Niemi et al, 2004; Ho et al, 2007), and pitavastatin (Oh et al, 2013)
The potential role of glycine amidinotransferase (GATM) genetic variations contributing to Statin-induced myotoxicity (SIM) was highlighted by Mangravite et al (2013), this study explored expression quantitative trait loci in SIM cases
Summary
Hydroxymethylglutaryl-coenzyme A reductase (HMG-CR) inhibitors, commonly known as statins, are indicated for hypercholesterolemia and atherosclerotic cardiovascular diseases (Grundy et al, 2019; Bartlomiejczyk et al, 2019). Genetic variation in enzymes and transporters to be discussed here have been reported to influence the concentration of statins in the body, which in turn may increase the risk of developing SIM. While the lactone moiety of statins is suggested to induce SIM (Skottheim et al, 2008), it is important to note that some of the mechanisms were hypothesized based on the notion that statin lactones readily penetrate into muscle cells, facilitated by their lipophilicity (Taha et al, 2016) This does not explain SIM cases associated with the use of the hydrophilic statins (rosuvastatin and pravastatin) and simvastatin acid (Link et al, 2008). The role of CYP2D6 in statin metabolism is minor (Figure 3), and research that has investigated the association between genetic variation in CYP2D6 and SIM has reported mixed conclusions (Table 3).
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