Genomewide Association Study of Statin‐Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink

Abstract

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirtyfive patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 −5 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 −9 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.The 3-hydroxy-3-methyl-glutaryl-coenzyme A inhibitors, or statins, are a widely prescribed class of drugs for the treatment of hyperlipidemia. Although generally well tolerated, a small proportion of patients can develop muscle-related adverse effects. 1 These can range from mild muscle pain without creatine kinase (CK) elevation, where causality can be difficult to assess,

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

“…In patients on 40 mg SVT daily, the myopathy relative risk remained but was halved to~2.6 (95% CI 1.3-5.0) per C allele, in keeping with a dose-related ADR [86]. This association between SVT myopathy and rs4149056 has been replicated [89,174] and confirmed in recent large meta-analyses [110,116]. Furthermore, rs4149056 has also been linked to milder adverse outcomes encompassing myalgia, prescription reductions and/or minor biochemical (e.g., CK) elevations indicative of SVT intolerance [69,85,113,175].…”

“…The GATM locus was associated with a reduced incidence of statin myopathy in two separate populations (combined SVT, ATV, PVT) with a meta-analysis OR for rs1719247 of 0.60 (95% CI 0.45-0.81, p = 6.0 × 10 −4 ) [126]. Several subsequent SRM studies of SRM have not replicated this finding [110,111,[240][241][242], although a recent candidate gene study of RVT myotoxicity in Han Chinese patients found a similar marginal protective effect of the GATM rs9806699 minor allele (p = 0.024) [109]. The lack of replication raises questions about the role of GATM in SRM; functional studies of GATM in human primary muscle cells may help resolve the discordant results.…”

“…Overall, it has been suggested that rs4149056 might be relevant for severe myopathy (e.g., CK > 10 × ULN) due to several statins, with an effect size likely greatest for SVT (or LVT) and lowest for FVT, based upon the degree to which the rs4149056 minor C allele increases exposure to each statin [110]. Nevertheless, rs4149056 has not yet been clearly associated with PVT myotoxicity [85,116], and whilst an association between rs4149056 and ATV myotoxicity has been suggested [85,113] or reported [114], several other studies found no evidence [89,110,116,174,[176][177][178]. Reasons for ongoing uncertainty regarding the role of rs4149056 in ATV myotoxicity include fewer ATV cases in studies (especially cases on high dose ATV) [89] and ATV appears less intrinsically myotoxic than SVT [165], as well as the impact of rs4149056 on exposure being smaller for ATV than SVT acid [172].…”

“…ABCB1 has three common SNPs, rs1128503 (1236T-C, synonymous), rs2032582 (missense, 2677T-G) and rs1045642 (synonymous, 3435T-C); TTT homozygotes have~55-60% increased exposure to both ATV and SVT acid [185]. The ABCB1 T alleles have been associated with symptom-independent elevated CK levels [117] and muscle symptoms [118,119] in some candidate gene studies, but not with prescribing changes suggestive of statin intolerance [121], nor in SRM GWAS [110,115].…”

“…Interestingly, carrying rs2231142 421A has been associated with an increased risk of myotoxicity with ATV [120], and in renal transplant recipients receiving FVT [105]. Both of these studies were small case control candidate gene studies and have not been confirmed in GWAS, although SRM GWAS analyses have included relatively few FVT cases to date [86,110,111,115].…”