Mechanisms of statin-induced myalgia assessed by physiogenomic associations

Abstract

Objective We investigated genetic variants predictive of muscular side effects in patients treated with statins. We utilized a physiogenomic approach to prototype a multi-gene panel correlated with statin-induced myalgia. Background Statin induced myalgia occurs in ∼10% of lipid clinic outpatients. Its clinical manifestation may depend in part upon gene variation from patient to patient. Methods We genotyped 793 patients (377 with myalgia and 416 without) undergoing statin therapy at four U.S. outpatient clinic sites to evaluate 31 candidate genes from the literature for their association with statin-induced common myalgia. Results Three previously hypothesized candidate genes were validated: COQ2 (rs4693570) encoding para-hydroxybenzoate-polyprenyltransferase, which participates in the biosynthesis of coenzyme Q10 (p<0.000041); ATP2B1 (rs17381194) which encodes a calcium transporting ATPase involved in calcium homeostasis (p<0.00079); and DMPK (rs672348) which encodes a protein kinase implicated in myotonic dystrophy (p<0.0016). Conclusions The candidate genes COQ2, ATP2B1, and DMPK, representing pathways involved in myocellular energy transfer, calcium homeostasis, and myotonic dystonia, respectively, were validated as markers for the common myalgia observed in patients receiving statin therapy. The three genes integrated into a physiogenomic predictive system could be relevant to myalgia diagnosis and prognosis in clinical practice.

Analysis of vitamin D levels in patients with and without statin-associated myalgia — A systematic review and meta-analysis of 7 studies with 2420 patients

“…In patients on high doses of statins, skeletal muscle levels of plant sterols might be increased by nearly 50%, which by inhibiting acetyl coenzyme A carboxylase, reduces fat synthesis, increases beta-oxidation, and results in muscle injury [24]. Others have suggested that individual genetic susceptibility plays an important role in statin-associated myalgia [25]. Finally, a potential mechanistic link for vit D is that the metabolism of some statins depends on cytochrome P450 3A4 (CYP3A4), which displays 25-hydroxylase activity in vitro [26].…”

Untitled

“…73 The one observational study demonstrated that the SLCO1B1 388A>G and 521T>C polymorphism were associated with a lower risk and higher risk of statin respectively stating role of SLCO1B1 polymorphism in statin tolerability 74 and risk is higher in native American having this polymorphism. 75 One more study identified three genes -COQ2, ATP2B1, and DMPK -that are accountable for pathways related to CoQ10 biosynthesis, calcium regulation in the body, and muscular dystonia, respectively, as markers for myalgia in patients having statin-associated myalgia. 76 …”

Statin-associated muscle symptoms EAS Consensus Panel paper focuses on this neglected patient group

“…Some variants of genes encoding drug transporters in both the liver and skeletal muscle, (most notably SLCO1B1, encoding OATP1B1), that increase serum statin concentration have been linked to muscle side effects [29]. Other candidate genes for statin-induced myalgia have been identified, including genotypes associated with statin-induced down regulation of expression of the gene encoding glycine amidinotransferase (GATM) [30]. GATM catalyses a critical step in hepatic and renal synthesis of creatine, used in muscle to form creatine phosphate, which is a major source of energy storage in muscle.…”