Cerivastatin (Baycol), an HMG-CoA reductase inhibitor (statin), was removed from the market because of an increased risk of rhabdomyolysis. In the original application, we conducted a case-control study of rhabdomyolysis to evaluate 3 pharmacokinetic candidate genes as risk factors. A non-synonymous variant (V174A, SLCO1B1*5 allele) in the hepatic transporter increased the rhabdomyolysis risk, a finding that we validated in functional studies. The completed candidate-gene work in pharmacokinetics leaves largely unexplained the biologic mechanisms by which some patients develop rhabdomyolysis, the signature toxicity of statins. While basic-science work has identified candidate pathways such as protein prenylation and cytosolic-calcium release that are likely to contribute to rhabdomyolysis risk, the mechanism of toxicity remains undefined, and the available studies provide no evidence that cerivastatin influences risk by different mechanisms than other statins. The bimodal response--a serious drug reaction in a small proportion of users and none in the vast majority of users--suggests genetic factors as a potential cause. Indeed, our genome-wide association study (GWAS) provides evidence of additional undiscovered genetic loci that influence rhabdomyolysis risk. For some people, statins may be the equivalent of fluorinated- inhalation anesthetics, which precipitate malignant hyperthermia (MH) in susceptible individuals. We hypothesize that statin-induced rhabdomyolysis resembles a heterogeneous Mendelian disorder that may have several forms caused by genetic variants at many loci in multiple genes. Examples that result from gene-environment interactions include MH [many rare variants in 6 loci] and phenylketonuria [100s of variants in several genes]. General support for this hypothesis comes from our GWAS, which identified a genome-wide significant marker in the ryanodine receptor 2 gene, an intra-cellular calcium-release channel. The primary aim of this whole-exome-sequencing case-control study of rhabdomyolysis is to identify and characterize the genetic determinants and biologic mechanisms that underlie the "pharmacodynamics" of this toxic drug-response phenotype. Data and specimens from the rhabdomyolysis cases were collected during the original grant period, and controls come from the CHS and ARIC studies. The primary analysis will take place in a set of candidate genes (n~500). Whole-exome sequencing is an efficient method to screen a large number of genes for uncommon and disabling genetic variants. To address the issue of generalizability, collaboration with investigators conducting a large case-control study of rhabdomyolysis (n=250 cases) in the United Kingdom, primarily in users of simvastatin and atorvastatin, will provide opportunities for replication, meta-analysis, and improved power. For validation and translational work, co- investigators will use variants discovered by exome sequencing and replicated by our UK collaborators to conduct basic-science studies and evaluate their function.

Public Health Relevance

The primary aim of this whole-exome-sequencing case-control study of rhabdomyolysis is to identify and characterize the genetic determinants and biologic mechanisms that underlie the pharmacodynamics of this toxic response to lipid-lowering statin drugs. The genes and the mechanisms identified in this study of rhabdomyolysis may also be important for the more mild and common forms of myopathy that are responsible for high rates of non-adherence with statin therapy. If genetic variants affect myopathy risk, screening for carriership may be appropriate for persons contemplating statins, especially as the use expands and the doses increase.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078888-07
Application #
8604724
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Jaquish, Cashell E
Project Start
2005-01-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
7
Fiscal Year
2014
Total Cost
$582,944
Indirect Cost
$63,267
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Sharfstein, Joshua M; Psaty, Bruce M (2016) Evaluation of the Cardiovascular Risk of Naltrexone-Bupropion: A Study Interrupted. JAMA 315:984-6
Floyd, James S; Brody, Jennifer A; Tiniakou, Eleni et al. (2016) Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy. Muscle Nerve 54:142-4
Psaty, Bruce M; Shah, Sanjiv J; Gottdiener, John (2015) Letter by Psaty et al regarding article, "Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes". Circulation 131:e343
Psaty, Bruce M; Platt, Richard; Altman, Russ B (2015) Neurotoxicity of generic anesthesia agents in infants and children: an orphan research question in search of a sponsor. JAMA 313:1515-6
Floyd, James S; Bis, Joshua C; Brody, Jennifer A et al. (2014) GATM locus does not replicate in rhabdomyolysis study. Nature 513:E1-3
Psaty, Bruce M; Weiss, Noel S (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol: a fresh interpretation of old evidence. JAMA 311:461-2
Floyd, James S; Psaty, Bruce M (2014) The potential risks of expedited approval of drugs for acute bacterial infections. JAMA Intern Med 174:1436-7
Psaty, Bruce M; Goodman, Steven N; Breckenridge, Alasdair (2013) Advances in regulatory science at the Food and Drug Administration. JAMA 309:2103-4
Psaty, Bruce M; Larson, Eric B (2013) Investments in infrastructure for diverse research resources and the health of the public. JAMA 309:1895-6
Psaty, Bruce M; Sitlani, Colleen (2013) The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science. Epidemiology 24:346-8

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