Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: a meta-analysis

Xiang, Qian; Chen, Shuqing; Ma, Lei; Hu, Kun; Zhang, Zhuo; Mu, Guangyan; Xie, Qiufen; Zhang, Xiaodan; Chen, Yimin

doi:10.1038/s41397-018-0054-0

Cited by 42 publications

(29 citation statements)

References 32 publications

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“…Our data concur with a previous statin myopathy GWAS, as well as our own pilot data and other candidate gene studies, that the SLCO1B1 c.521C>T polymorphism (rs4149056) is the predominant genetic risk factor for statin‐induced myopathy. Our finding is also consistent with a recent meta‐analysis of 14 studies comprising 3,265 myopathy patients and 7,743 controls . Additionally, previously reported associations in the GATM , COQ2 , and human eyes shut ortholog gene loci were not replicated.…”

Section: Discussionsupporting

confidence: 92%

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

Carr

Francis

Jorgensen

et al. 2019

Clin Pharma and Therapeutics

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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,

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Section: Discussionsupporting

confidence: 92%

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

Carr

Francis

Jorgensen

et al. 2019

Clin Pharma and Therapeutics

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“…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].…”

Section: Slco1b1 Influx Transportermentioning

confidence: 67%

“…Intriguingly, SLCO1B1 rs4149056 has been recently associated with RVT myotoxicity (a composite of myalgias to rhabdomyolysis) in Han Chinese patients [109,176], although it was not previously associated with myalgias in patients of European descent receiving RVT [112]. A recent meta-analysis, largely including these studies, further suggested an association between rs4149056 and RVT myotoxicity [116]. Given the increased RVT exposure reported in Asian compared to Caucasian patients, which is partially but not completed explained by ABCG2 rs2231142 (see Section 6.2.4) [80], Asian patients are perhaps more sensitive to further SLCO1B1-mediated increases in RVT exposure.…”

Section: Slco1b1 Influx Transportermentioning

confidence: 99%

“…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].…”

Section: Slco1b1 Influx Transportermentioning

confidence: 99%

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

Turner

Pirmohamed

2019

JCM

132

126

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Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.

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“…Studies showed that patients with the allele of 521 C in SLCO1B1 were only associated with the increased risk of myopathy in patients with simvastatin therapy, but not with atorvastatin. Whether 521 C has such influence in patients with rosuvastatin therapy is still controversial . Besides, it is also proved that East Asians had a higher drug exposure and a lower oral clearance rate than Caucasians.…”

Section: Resultsmentioning

confidence: 99%

Pharmacogenetics of statins treatment: Efficacy and safety

Guan

et al. 2019

J Clin Pharm Ther

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What is known and objective: Statins are widely used worldwide in the prevention and treatment of coronary atherosclerotic heart disease and ischaemic stroke.However, in clinical application, statins have shown great individual differences in terms of the efficacy and safety, some of which are related to genetic factors. The purpose of this article was to summarize the recent advances about the correlation between gene polymorphisms and the efficacy/safety of statins. Methods:We searched the databases including PharmGKB and PubMed (published before June 2019) using the keywords such as 'statin', 'gene polymorphism' and 'SNP' and obtained more than 100 articles. In this review, we described the clinical studies of genetic variants associated with both the efficacy and adverse reactions of statins.We also clarified the importance of taking pharmacogenetic variation into account to improve the clinical application of statins. Results and discussion:The available data were collected and analysed to present the polymorphisms of candidate genes encoding the most promising proteins including SLCO1B1 (encoding uptake transporters); ABCB1, ABCC2, ABCG2 (encoding effluent transporter); APOE, APOA5 (encoding apolipoprotein); genes encoding cytochrome P450 enzyme system; KIF6, HMGCR, LDLR, LPA, PCSK9, COQ2, CETP, etc These genes were proved to be related to the pharmacodynamics and pharmacokinetics of statins, thus affecting the efficacy and safety. What is new and conclusion:In this paper, the correlation between gene polymorphisms and the efficacy/safety of statins was summarized. The authors reached a consensus that the variants of the genes encoding uptake and effluent transporters have the most effect on the efficacy/safety of statins. It pointed out that it is desirable to do genetic testing of these transporter genes to reduce the incidence of myopathy or to achieve better outcomes before patients use statins, especially in the regions with high frequency of risk allele. K E Y W O R D S cytochrome P450, gene polymorphism, pharmacogenetics, statins, transporter | 859 GUAN et Al.

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Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: a meta-analysis

Cited by 42 publications

References 32 publications

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

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

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

Pharmacogenetics of statins treatment: Efficacy and safety

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