Genetic Susceptibility to Statin-Induced Myopathy

Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (Vladutiu et al.,2006). We also reported a patient with statin myopathy who had an RYR1 variant known to be causative of malignant hyperthermia susceptibility (MHS) (Vladutiu et al., 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (2006). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (2011). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173. ]]>
Two groups of individuals are included who have severe statin-induced myopathy. Individuals considered as having severe statin-induced myopathy must satisfy all the following criteria: self-reported muscle pain +/- weakness after taking statin and persistent symptoms post-therapy for at least 6 months. The first group is 20 individuals from 8 family groups in which the probands have severe statin-induced myopathy +/- elevated plasma CK. The second group consists of 26 unrelated individuals with severe statin-induced myopathy who have muscle pain and/or weakness attributed solely to statin therapy and plasma creatine kinase (CK) levels > 5 times the upper limit of normal (ULN). Age under 65 when symptoms started.]]>
The laboratory's interest in statin-induced myopathy began with an increasing number of referrals to our clinical diagnostic laboratory from patients who had been taking statins and developed muscle symptoms attributed to statin therapy. We hypothesized that an increased number of these individuals would have greater genetic liability for underlying muscle disease than found in the general population. We found an increase in underlying genetic susceptibility to muscle disease first in these clinical cases and then in preliminary case-control studies comparing cases with statin-tolerant controls. In a larger study, we collaborated with 5 medical centers across the U.S. and Canada recruiting approximately 900 cases and controls from which we have obtained a large volume of data using a combination of chip technology, whole exome and whole genome sequencing. Genetic liability involving variants in many genes underlies risk for severe statin myopathy. ]]>