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.

Trial registration: ClinicalTrials.gov NCT00767130.

Conflict of interest statement

Conflict of Interest: Neither Dr. Thompson, Dr. Kane, Dr. Wu, or Dr. Gordon have consulting or other financial arrangements with Genomas. Drs. Ruaño and Windemuth are employees and shareholders of Genomas, Inc. Mr. Kocherla and Ms. Bogaard are full time employees of Genomas, Inc. Drs. Holford and Seip are consultants to Genomas, Inc. Dr. Thompson has received speaking honoraria or consulting fees from GlaxoSmithKline, Merck, Roche, Pfizer, Astra Zeneca B. Braun, Schering-Plough, Takeda, and Abbott.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Figures

Figure 1

Genomic environment and effect on myalgia for COQ2. The plot (left) shows log-scores of association for all SNPs versus chromosomal location within 200 kb of the index SNP location, and bar graph (right) shows the effect of the variant allele on the probability of myalgia in subgroups of patients taking one of the three major statins. Gene names are LIN54, C. elegans, homolog of; COPS4; PLAC8, placenta specific gene 8; COQ2, para-hydroxybenzoate-polyprenyltransferase; HPSE, heparanase. For bar graph, abbreviations for statin names are SIM, simvastatin; ATO, atorvastatin, and ROS, rosuvastatin.

Figure 2

Effect of the validated SNP associations on the probability of myalgia. Panels A-C: the fraction of myalgia patients among the three different genotypes for each marker. Gene names are COQ2, para-hydroxybenzoate-polyprenyltransferase; DMPK, myotonin, protein kinase; ATP2B1, Plasma membrane calcium-transporting ATPase 1). Panel D: the fraction of myalgia patients among groups having 0, 1, 2, 3, 4, 5, or 6 of the risk alleles, regardless from which of the three genes. 95% confidence intervals are given for the true fraction based on the patient count in each group.