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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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“However, the use of a mechanistic PBPK model can point out the relation between subgroup and genotype which makes our Bayesian-PBPK approach a suitable alternative to rather phenomenological methods (Link et al., 2008).”
Support of drug therapy using functional foods and dietary supplements: focus on statin therapy
Eussen, S. R. B. M., Klungel, O. H., Garssen, J., Verhagen, H., van Kranen, H. J., Loveren, H. V., & Rompelberg, C. J. M. (2010) · British Journal Of Nutrition · doi:10.1017/s0007114509993230 · Cited by 52
“Also studies towards the effects of genetic polymorphisms are warranted as indicated by, for example, the association between variants in SLCO1B1 (solute carrier organic anion transporter family, member 1B1) and increased risk of statin-induced myopathy((128)), the association between ABCA1 expression and cholesterol…”
BackgroundImportant drug-micronutrient interactions: A selection for clinical practice
Gröber, U., Schmidt, J., & Kisters, K. (2018) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2018.1522613 · Cited by 54
Pharmacogenomic Genome-Wide Association Studies: Lessons Learned Thus Far
Crowley, J. J., Sullivan, P. F., & McLeod, H. L. (2009) · Pharmacogenomics · doi:10.2217/14622416.10.2.161 · Cited by 52
Pharmacogenomics: Current State-of-the-Art
Carr, D. F., Alfirevic, A., & Pirmohamed, M. (2014) · Genes · doi:10.3390/genes5020430 · Cited by 52
“521T>C/*5) [6]”
Assessment of gadoxetate DCE‐MRI as a biomarker of hepatobiliary transporter inhibition
Ulloa, J. L., Stahl, S. H., Yates, J. W. T., Woodhouse, N., Kenna, J. G., Jones, H. B., Waterton, J. C., & Hockings, P. D. (2013) · NMR in Biomedicine · doi:10.1002/nbm.2946 · Cited by 52
Evidence for Clinical Implementation of Pharmacogenomics in Cardiac Drugs
Kaufman, A. L., Spitz, J. A., Jacobs, M., Sorrentino, M. J., Yuen, S., Danahey, K., Saner, D., Klein, T. E., Altman, R. B., Ratain, M. J., et al. (2015) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2015.03.016 · Cited by 51
PERSONALIZED MEDICINE: STATE-OF-THE-ART AND PROSPECTS
Dedov, I. I., Tyul'pakov, A. I., Chekhonin, V. P., Baklaushev, V. P., Archakov, A. I., & Moshkovskii, S. A. (2012) · Annals of the Russian academy of medical sciences · doi:10.15690/vramn.v67i12.474 · Cited by 54
Yin, J., Huang, Q., Zhao, Y.-C., Zhou, H.-H., & Liu, Z. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038150 · Cited by 51
“On the other hand, GWAS have been successfully used in disease susceptibility and pharmacogenetic research [47–50].”
Atorvastatin: safety and tolerability
Athyros, V. G., Τζιόμαλος, Κ., Karagiannis, A. I., & Mikhailidis, D. P. (2010) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2010.495385 · Cited by 53
“Interim analyses revealed a strong association of myopathy during simvastatin 80 mg/day treatment with co-administration of amiodarone [50] and with the SLCO1B1 single-nucleotide polymorphism of the rs4363657 gene on chromosome 12, which has been shown to regulate the hepatic uptake of statins [50].”
BackgroundPharmacogenetics of Membrane Transporters: A Review of Current Approaches
Sissung, T. M., Goey, A. K. L., Ley, A. M., Strope, J. D., & Figg, W. D. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-0956-8_6 · Cited by 54
“For instance, all statins are transported from the circulation into the liver by OATP1B1, which affects the systemic exposure to many statins and thereby statininduced myopathy [30].”
BackgroundPrecision medicine: from pharmacogenomics to pharmacoproteomics
Chambliss, A. B., & Chan, D. W. (2016) · Clinical Proteomics · doi:10.1186/s12014-016-9127-8 · Cited by 52
Genetics of Patent Ductus Arteriosus Susceptibility and Treatment
Hajj, H., & Dagle, J. M. (2012) · Seminars in Perinatology · doi:10.1053/j.semperi.2011.09.019 · Cited by 52
Terada, T., & Hira, D. (2015) · Journal of Gastroenterology · doi:10.1007/s00535-015-1061-4 · Cited by 50
Targeting the airway smooth muscle for asthma treatment
Camoretti-Mercado, B. (2009) · Translational research · doi:10.1016/j.trsl.2009.06.008 · Cited by 50
Peyser, B., Perry, E. P., Singh, K., Gill, R. D., Mehan, M. R., Haga, S. B., Musty, M. D., Milazzo, N. A., Savard, D., Li, Y., et al. (2018) · Circulation Genomic and Precision Medicine · doi:10.1161/circgen.118.002228 · Cited by 50
Genetic variability and population diversity of the human SLCO (OATP) transporter family
Zhang, B., & Lauschke, V. M. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.10.017 · Cited by 50
Magavern, E. F., Kaski, J. C., Turner, R. M., Drexel, H., Janmohamed, A., Scourfield, A., Burrage, D., Floyd, C. N., Adeyeye, E., Tamargo, J. L., et al. (2021) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvab018 · Cited by 55
Pharmacogenomics in the era of next generation sequencing – from byte to bedside
Russell, L. E., Zhou, Y., Almousa, A. A., Sodhi, J. K., Nwabufo, C. K., & Lauschke, V. M. (2021) · Drug Metabolism Reviews · doi:10.1080/03602532.2021.1909613 · Cited by 52
Expert opinion: the therapeutic challenges faced by statin intolerance
Patel, J., Martin, S. S., & Banach, M. (2016) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2016.1197202 · Cited by 51
“The risk of myopathy is greater per copy of the SLCO1B1*5 allele and appears to be statin specific [120].”
BackgroundIncreased cardiovascular risk in patients with chronic kidney disease
Vondenhoff, S., Schunk, S. J., & Noels, H. (2024) · Herz · doi:10.1007/s00059-024-05235-4 · Cited by 49
Clarke, J., Hardwick, R. N., Lake, A. D., Canet, M. J., & Cherrington, N. J. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.211284 · Cited by 49
“ABBREVIATIONS: ADR, adverse drug reaction; AUC, area under the curve; Cl, clearance; ERK1, extracellular signal-regulated kinase 1; MCD, methionine and choline deficient; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OATP, organic anion transporting polypeptide; SIM, simvastatin; SIM-d6,…”
BackgroundInfluentialTsai, C., Hsieh, C.-S., Chang, S., Chuang, E. Y.-Y., Ueng, K.-C., Tsai, C., Lin, T., Wu, C., Lee, J.-K., Lin, L., et al. (2016) · Nature Communications · doi:10.1038/ncomms10190 · Cited by 49
Robinson, J. R., Denny, J. C., Roden, D. M., & Driest, S. L. V. (2017) · Clinical and Translational Science · doi:10.1111/cts.12522 · Cited by 51
“65 While the variant allele frequency of this significant polymorphism is 0.13 in European populations, carriage of the variant allele resulted in an 18% incidence of myopathy over 5 years, with 60% of cases attributable to the variant allele.”
BackgroundInfluentialCrowe, A., Zheng, W., Miller, J. L., Pahwa, S., Alam, K., Fung, K., Rubin, E., Yin, F., Ding, K., & Yue, W. (2019) · Pharmaceutical Research · doi:10.1007/s11095-019-2634-3 · Cited by 49
Impact of ABCC2, ABCG2 and SLCO1B1 Polymorphisms on the Pharmacokinetics of Pitavastatin in Humans
Oh, E. S., Kim, C. O., Cho, S. K., Park, M. S., & Chung, J. (2012) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.dmpk-12-rg-068 · Cited by 49
Genetic testing in renal disease
Bockenhauer, D., Medlar, A., Ashton, E., Kleta, R., & Lench, N. (2012) · Pediatric nephrology (Berlin, West) · doi:10.1007/s00467-011-1865-2 · Cited by 49
Ito, M. K., Maki, K. C., Brinton, E. A., Cohen, J. D., & Jacobson, T. A. (2013) · Journal of clinical lipidology · doi:10.1016/j.jacl.2013.10.006 · Cited by 48
König, J., Glaeser, H., Keiser, M., Mandery, K., Klotz, U. E., & Fromm, M. F. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.034991 · Cited by 48
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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