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SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study
Open accessAbstract
BACKGROUND: Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. METHODS: We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. RESULTS: The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. CONCLUSIONS: We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.)
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“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%.111”
From Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management (2015) · cites this paper as [111]
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Hur, J., Liu, Z., Tong, W., Laaksonen, R., & Bai, J. P. F. (2014) · Chemical Research in Toxicology · doi:10.1021/tx400409c · Cited by 31
Luzum, J. A., Theusch, E., Taylor, K. D., Wang, A., Sadée, W., Binkley, P. F., Krauss, R. M., Medina, M. W., & Kitzmiller, J. P. (2015) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000246 · Cited by 32
“However, compensating for the increased dose requirements in the high-ratio group by increasing the SV dose would be risky because this group already has increased risk for myopathy because of their SLCO1B1 521C carrier genotype.(22) Alternatively, patients with plasma SVA/SV ,1 (low-ratio group; CYP3A4*1/*22 and SLCO…”
BackgroundLeveraging human genetics to guide drug target discovery
Stitziel, N. O., & Kathiresan, S. (2016) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2016.08.008 · Cited by 31
“risk of developing statin-induced myopathy [40].”
IGF-1 prevents simvastatin-induced myotoxicity in C2C12 myotubes
Bonifacio, A., Sanvee, G. M., Brecht, K., Kratschmar, D. V., Odermatt, A., Bouitbir, J., & Krähenbühl, S. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1871-z · Cited by 31
“Statins are mitochondrial toxicants (Bouitbir et al. 2012; Kaufmann et al. 2006) and have been shown to increase mitochondrial ROS production (Bouitbir et al. 2016; Kaufmann et al. 2006).”
BackgroundBai, X., Zhang, B., Wang, P., Wang, G., Li, J., Wen, D., Long, X.-Z., Sun, H., Liu, Y., Huang, M., et al. (2018) · Acta Pharmacologica Sinica · doi:10.1038/s41401-018-0013-y · Cited by 31
Cardiovascular Pharmacogenomics: Does It Matter If You're Black or White?
De, T., Park, C. S., & Perera, M. A. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021154 · Cited by 34
“9 for the homozygous CC genotype as compared with TT homozygotes (3).”
BackgroundGenetic and Developmental Factors in Chronic Kidney Disease Hotspots
Friedman, D. J., & Luyckx, V. A. (2019) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2019.02.002 · Cited by 31
Pharmacokinetic Pharmacogenomics
Alsanosi, S., Skiffington, C., & Padmanabhan, S. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-386882-4.00017-7 · Cited by 31
Escalante, E. J., de Lima, J. N. G., Ronsano, J. B. M., Torres-Bondia, F. I., & Segarra-Medrano, A. (2020) · Kidney International Reports · doi:10.1016/j.ekir.2020.09.046 · Cited by 31
Effect of Pharmacogenetic Testing for Statin Myopathy Risk vs Usual Care on Blood Cholesterol
Vassy, J. L., Gaziano, J. M., Green, R. C., Ferguson, R. E., Advani, S., Miller, S. J., Chun, S., Hage, A. K., Seo, S.-J., Majahalme, N., et al. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2020.27092 · Cited by 33
“Intervention The SLCO1B1 results were entered as structured data in the EHR after a median (interquartile range) turnaround time of 8 (7-9) days after enrollment of each patient in the intervention group.”
MethodDiabetes Mellitus Reduces the Clearance of Atorvastatin Lactone
Dostálek, M., Sam, W. J., Paryani, K. R., Macwan, J. S., Gohh, R., & Akhlaghi, F. (2012) · Clinical Pharmacokinetics · doi:10.1007/bf03261933 · Cited by 32
“Moreover, in patients receiving simvastatin, genetic polymorphism of solute carrier organic anion transporter family member 1B1 (SLCO1B1 encoding organic anion transporting polypeptide 1B1 [OATP1B1]) was strongly related to the risk of myopathy.([12]) However, physiological or pathological conditions such as aging or…”
BackgroundCardiovascular pharmacogenomics: current status and future directions
Roden, D. M. (2015) · Journal of Human Genetics · doi:10.1038/jhg.2015.78 · Cited by 32
Using Genetic Diagnosis to Determine Individual Therapeutic Utility
Caskey, C. T. (2010) · Annual Review of Medicine · doi:10.1146/annurev-med-011209-132719 · Cited by 31
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Adverse Drug Reactions: History, Terminology, Classification, Causality, Frequency, Preventability
Aronson, J. K. (2011) · Wiley eBooks · doi:10.1002/9780470975053.ch1 · Cited by 31
Hoefsmit, E. P., Rozeman, E. A., Haanen, J. B. A. G., & Blank, C. U. (2019) · ESMO Open · doi:10.1136/esmoopen-2018-000472 · Cited by 29
Genetic Testing in Hyperlipidemia
Bilen, O., Pokharel, Y., & Ballantyne, C. M. (2016) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2015.09.009 · Cited by 30
Sadler, M. C., Apostolov, A. M., Cevallos, C., Auwerx, C., Ribeiro, D. M., Altman, R. B., & Kutalik, Z. (2025) · Nature Communications · doi:10.1038/s41467-025-58152-3 · Cited by 32
“…fi ed, also known as Val174Ala or SLCO1B1*5, has previously been associated with LDL-C statin response 4,30 as well as myopathy 31 , a rare but well-described side effect that has been attributed to increased statin blood concentrations due to the reduced uptake capacity of the encoded protein 29 .”
Yang, G.-P., Yuan, H., Tang, B., Zhang, W., Wang, L., Huang, Z., Ouyang, D., Zhang, G., & Zhou, H. (2010) · Acta Pharmacologica Sinica · doi:10.1038/aps.2009.203 · Cited by 30
The Use of Genomic Information to Optimize Cancer Chemotherapy
Innocenti, F., Cox, N. J., & Dolan, M. E. (2011) · Seminars in Oncology · doi:10.1053/j.seminoncol.2011.01.005 · Cited by 30
“Several recent GWAS of drug response in areas outside of oncology indicate that genomewide significance (p<10-7) can be achieved with 50-85 cases in a case-control design (89, 90).”
Nandish, S., Wyatt, J., Bailon, O., Smith, M., OLIVEROS, R. A., & CHILTON, R. J. (2011) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2011.03.015 · Cited by 29
Kirhmajer, M. V., Šarinić, V. M., Šimičević, L., Ladić, I., Putarek, K., Banfić, L., & Božina, N. (2018) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13035 · Cited by 30
Statin Intolerance Clinical Guide 2018
Kajinami, K., Tsukamoto, K., Koba, S., Inoue, I., Yamakawa, M., Suzuki, S., Hamano, T., Saito, H., Saito, Y., Masuda, S., et al. (2019) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.50948 · Cited by 32
Role of Genetic Variations in the Hepatic Handling of Drugs
Marı́n, J. J. G., Serrano, M. A., Monte, M. J., Sánchez-Martín, A., Temprano, Á. G., Briz, Ó., & Romero, M. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082884 · Cited by 32
“Although low clinical impact of these SNPs for many drugs that are substrates of OATP1B1 has been found, they markedly affect the pharmacokinetics of statins [13].”
BackgroundIdentifying statin-associated autoimmune necrotizing myopathy
Albayda, J., & Christopher‐Stine, L. (2014) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.81a.13158 · Cited by 30
Metadata
- Authors
- The SEARCH Collaborative Group
- Affiliations
- University of Oxford (GB)
- Corresponding author
- The SEARCH Collaborative Group
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-08-21
- Volume
- 359
- Issue
- 8
- Pages
- 789-799
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1604547439
- Cited by
- 2,043
- References
- 27
- Citations by year
- 2026: 54 · 2025: 63 · 2024: 56 · 2023: 67 · 2022: 89 · 2021: 74 · 2020: 93 · 2019: 97 · 2018: 97 · 2017: 91 · 2016: 125 · 2015: 123 · 2014: 151 · 2013: 178 · 2012: 181
- FWCI
- 152.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- British Heart Foundation
- Medical Research Council (MC_EX_G0801669)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- statin-induced myopathy, SLCO1B1, OATP1B1, simvastatin, rs4149056, single nucleotide polymorphisms, statin metabolism, hepatic uptake, LDL cholesterol lowering, genetic susceptibility, drug-induced myopathy, linkage disequilibrium, replication study, statin dose
- MeSH terms
- Aged, Arterial Occlusive Diseases, Chromosomes, Human, Pair 12, Diabetes Mellitus, Female, Genetic Markers, Genotype, Humans, Male, Middle Aged, Muscular Diseases, Myocardial Infarction, Risk, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Polymorphism, Single Nucleotide, Organic Anion Transporters, Liver-Specific Organic Anion Transporter 1
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