29 Jun Pharmacogenomic Study of Statin-Associated Muscle Symptoms in the ODYSSEY OUTCOMES Trial
Circulation: Genomic and Precision Medicine, <a href=»https://www.ahajournals.org/toc/circgen/15/3″>Volume 15, Issue 3</a>, Page e003503, June 1, 2022.
Background:Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the p.Val174Ala missense variant inSLCO1B1and SAMS in simvastatin-treated subjects; however, evidence for genetic predictors of SAMS in atorvastatin- or rosuvastatin-treated subjects is currently lacking.Methods:ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; n=18 924) was a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of alirocumab (a PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor) in acute coronary syndrome patients receiving high-intensity statin therapy. The goal of this pharmacogenomic analysis was to identify genetic variants associated with atorvastatin- and rosuvastatin-mediated SAMS among ODYSSEY OUTCOMES subjects who consented to participate in the genetic study (n=11 880). We performed multi-ancestry exome-wide and genome-wide association studies and gene burden analysis across 2 phenotypes (clinical SAMS [n=10 617] and creatine kinase levels [n=9630]).Results:A novel genome-wide significant association for an intronic variant (rs6667912) located withinTMEM9(odds ratio [95% CI], 1.39 [1.24–1.55];P=3.71×10−8) for patients with clinical SAMS (cases=894, controls=9723) was identified. This variant is located ≈30 kb upstream ofCACNA1S, a locus associated with severe SAMS. We replicated 2 loci, atLINC0093andLILRB5, previously associated with creatine kinase levels during statin treatment. No association was observed between p.Val174Ala (rs4149056) inSLCO1B1and SAMS (odds ratio [95% CI], 1.03 [0.90–1.18];P=0.69).Conclusions:This study comprises the largest discovery exome-wide and genome-wide association study for atorvastatin- or rosuvastatin-mediated SAMS to date. These novel genetic findings may provide biological/mechanistic insight into this drug-induced toxicity, and help identify at-risk patients before selection of lipid-lowering therapies.