SLCO1B1 Polymorphisms and Statin-Induced Myopathy

DECEMBER 4, 2013 · RISK PREDICTION

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Alison Stewart

ABSTRACT

Statin drugs are highly effective in lowering blood concentrations of LDL-cholesterol, with concomitant reduction in risk of major cardiovascular events. Although statins are generally regarded as safe and well-tolerated, some users develop muscle symptoms that are mostly mild but in rare cases can lead to life-threatening rhabdomyolysis. The SEARCH genome-wide association study, which has been independently replicated, found a significant association between the rs4149056 (c.521T>C) single-nucleotide polymorphism (SNP) in the SLCO1B1 gene, and myopathy in individuals taking 80 mg simvastatin per day, with an odds ratio of 4.5 per rs4149056 C allele. The purpose of this paper is to assemble evidence relating to the analytical validity, clinical validity and clinical utility of using SLCO1B1 rs4149056 genotyping to inform choice and dose of statin treatment, with the aim of minimising statin-induced myopathy and increasing adherence to therapy. Genotyping assays for the rs4149056 SNP appear to be robust and accurate, though direct evidence for the performance of array-based platforms in genotyping individual SNPs was not found. Using data from the SEARCH study, calculated values for the clinical sensitivity, specificity, positive- and negative-predictive values of a test for the C allele to predict definite or incipient myopathy during 5 years of 80 mg/day simvastatin use were 70.4%, 73.7%, 4.1% and 99.4% respectively. There is a need for studies comparing the clinical validity of SLCO1B1 rs4149056 genotyping with risk scores for myopathy based on other factors such as racial background, statin type and dose, gender, body mass index, co-medications and co-morbidities. No direct evidence was found for clinical utility of statin prescription guided by SLCO1B1 genotype.

FUNDING STATEMENT

The author is a paid contractor of McKing Consulting Corporation working with the Office of Public Health Genomics, Centers for Disease Control and Prevention. This article was created during the course of that work.

CLINICAL SCENARIO

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors which reduce the risk of coronary events and death by lowering blood concentrations of low density lipoprotein cholesterol (LDL-c).¹^,²^,³^,⁴ They are generally regarded as safe and well tolerated. However, some patients experience adverse muscle symptoms; these are mostly relatively mild but, in rare cases, severe muscle damage with renal failure (rhabdomyolysis) may occur (reviewed in ⁵^,⁶). Recently, an autoimmune form of necrotising myositis has also been identified as a rare statin-associated myopathy (reviewed in ⁷).

There are no standard definitions or terminology for statin-associated muscle symptoms (Table 1⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³), an issue that complicates attempts to establish the incidence of the condition. There is also uncertainty about the relationship between clinical symptoms, and levels of biochemical markers of muscle toxicity such as serum creatine kinase (CK). Most myopathy reported by statin users takes the form of myalgia: muscle ache, tenderness or weakness without elevated CK. Biochemically confirmed myopathy is generally associated with CK levels at least 10 times the upper limit of normal (ULN). Some classifications include an intermediate phenotype (“incipient” myopathy in the large SEARCH study,⁸ myositis in the ACC/AHA/NHLBI classification,¹⁰ hyperCKemia in the Canadian Working Group consensus,¹³ “mild myopathy” or “mild intolerance” in some other studies) with CK levels generally between 3× and 10×ULN, with or without muscle symptoms, and, in some cases, an additional criterion of elevated serum alanine aminotransferase (AAT).⁸ Rhabdomyolysis is diagnosed by CK levels substantially above 10×ULN (>50×ULN in the FDA classification), together with symptoms such as brown urine, elevated serum creatine and evidence of organ damage. Despite the inclusion of CK levels in most diagnostic criteria for myopathy, there is some evidence that clinically significant muscle toxicity can occur without increase in CK levels.¹⁴