Statin-Associated Muscle Symptoms: Impact on Statin Therapy
Statin-Associated Muscle Symptoms: Impact on Statin Therapy
While genetic testing in patients with statin myopathy has not yet become commonplace, there are some clear genetic signals, with variants of genes encoding drug transporters in both the liver and skeletal muscle that increase serum statin concentration linked to muscle side effects (see Supplementary material online, Table S5 http://eurheartj.oxfordjournals.org/content/suppl/2015/02/18/ehv043.DC1). The most significant associations have been single-nucleotide polymorphisms (SNPs) in SLCO1B1, encoding OATP1B1. The SEARCH genome-wide association study of SLCO1B1 variants identified a defective rs4149056 SNP in strong linkage disequilibrium with the c.521T_C SNP, which, in homozygotes, was associated with an 18% risk of muscle symptoms with high-dose simvastatin compared with heterozygotes (3%); in those without risk alleles, the risk of muscle symptoms was 0.6%.
An increased frequency of pathogenic variants in muscle-disease-associated genes has been reported, with a 13- to 20-fold higher incidence in subjects with severe myopathy compared with the general population. In one study, 17.1% of patients with severe statin myopathy and 16.1% of patients with non-statin-induced exertional rhabdomyolysis had pathogenic variants in 12 muscle disease genes studied vs. 4.5% of statin-tolerant controls. Other candidate genes for statin-induced myalgia have been identified, each with a plausible pathophysiological relationship to muscle metabolism, but without adequate evidence to support their clinical relevance. Glycine amidinotransferase (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. Two independent studies showed that genotypes associated with statin-induced down-regulation of expression of the gene encoding GATM were associated with protection from statin-induced myopathy. Other investigators, however, were unable to replicate the association between the rs9806699 GATM SNP and statin myopathy. Clearly, further studies will be required to determine a mechanistic basis for a contribution of genetic variation in GATM to the risk of SAMS. Potential non-disease candidate genes whose products might be determinants of statin-attributed muscle symptoms include those encoding enzymes involved in drug metabolism and disposition, mitochondrial function, or ubiquitination.
Genotyping of patients with personal or family histories of muscle disease who develop SAMS has been suggested as a means of diagnosing underlying muscle disease. Candidates for genetic testing may also include patients with documented prolonged statin-associated muscle symptoms >6 months post-therapy, and symptomatic patients with plasma CK >4× ULN. Targeted next-generation sequencing of muscle disease genes in these high-risk individuals will certainly become more prominent in diagnosing individuals at risk. Identification of underlying genetic risk factors may contribute to improved therapeutic compliance through careful monitoring of conservative therapy. At present, however, there is insufficient evidence to recommend genetic testing as a part of the diagnostic work-up of patients with SAMS.
Genetic Susceptibility to Statin-associated Muscle Symptoms
While genetic testing in patients with statin myopathy has not yet become commonplace, there are some clear genetic signals, with variants of genes encoding drug transporters in both the liver and skeletal muscle that increase serum statin concentration linked to muscle side effects (see Supplementary material online, Table S5 http://eurheartj.oxfordjournals.org/content/suppl/2015/02/18/ehv043.DC1). The most significant associations have been single-nucleotide polymorphisms (SNPs) in SLCO1B1, encoding OATP1B1. The SEARCH genome-wide association study of SLCO1B1 variants identified a defective rs4149056 SNP in strong linkage disequilibrium with the c.521T_C SNP, which, in homozygotes, was associated with an 18% risk of muscle symptoms with high-dose simvastatin compared with heterozygotes (3%); in those without risk alleles, the risk of muscle symptoms was 0.6%.
An increased frequency of pathogenic variants in muscle-disease-associated genes has been reported, with a 13- to 20-fold higher incidence in subjects with severe myopathy compared with the general population. In one study, 17.1% of patients with severe statin myopathy and 16.1% of patients with non-statin-induced exertional rhabdomyolysis had pathogenic variants in 12 muscle disease genes studied vs. 4.5% of statin-tolerant controls. Other candidate genes for statin-induced myalgia have been identified, each with a plausible pathophysiological relationship to muscle metabolism, but without adequate evidence to support their clinical relevance. Glycine amidinotransferase (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. Two independent studies showed that genotypes associated with statin-induced down-regulation of expression of the gene encoding GATM were associated with protection from statin-induced myopathy. Other investigators, however, were unable to replicate the association between the rs9806699 GATM SNP and statin myopathy. Clearly, further studies will be required to determine a mechanistic basis for a contribution of genetic variation in GATM to the risk of SAMS. Potential non-disease candidate genes whose products might be determinants of statin-attributed muscle symptoms include those encoding enzymes involved in drug metabolism and disposition, mitochondrial function, or ubiquitination.
Genotyping of patients with personal or family histories of muscle disease who develop SAMS has been suggested as a means of diagnosing underlying muscle disease. Candidates for genetic testing may also include patients with documented prolonged statin-associated muscle symptoms >6 months post-therapy, and symptomatic patients with plasma CK >4× ULN. Targeted next-generation sequencing of muscle disease genes in these high-risk individuals will certainly become more prominent in diagnosing individuals at risk. Identification of underlying genetic risk factors may contribute to improved therapeutic compliance through careful monitoring of conservative therapy. At present, however, there is insufficient evidence to recommend genetic testing as a part of the diagnostic work-up of patients with SAMS.
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