Cited by 2,043Pharmacogenetics and Drug MetabolismLipoproteins and Cardiovascular HealthGenetic Associations and Epidemiology

The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.

SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study

Open access

The SEARCH Collaborative Group·2008·New England Journal of Medicine

DOI 10.1056/nejmoa0801936

Open this paper in CoChat — free account Open PDF

Abstract

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.)

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1056/nejmoa0801936

Cites

28 of 28 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J. C., Fry, B., Maller, J., & Daly, M. J. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth457 · Cited by 14,551
Principal components analysis corrects for stratification in genome-wide association studies
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006) · Nature Genetics · doi:10.1038/ng1847 · Cited by 10,248
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial
(2002) · The Lancet · doi:10.1016/s0140-6736(02)09327-3 · Cited by 6,992
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins
(2005) · The Lancet · doi:10.1016/s0140-6736(05)67394-1 · Cited by 6,848
A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858
Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
Cannon, C. P., Braunwald, E., McCabe, C. H., Rader, D. J., Rouleau, J. L., Belder, R., Joyal, S. V., Hill, K. A., Pfeffer, M. A., & Skene, A. M. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040583 · Cited by 4,938
Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease
LaRosa, J. C., Grundy, S. M., Waters, D. D., Shear, C., Barter, P., Fruchart, J.-C., Gotto, A. M., Greten, H., Kastelein, J. J. P., Shepherd, J., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050461 · Cited by 3,489
High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction<SUBTITLE>The IDEAL Study: A Randomized Controlled Trial</SUBTITLE>
Pedersen, T. R. (2005) · JAMA · doi:10.1001/jama.294.19.2437 · Cited by 1,548

Flagged first, then by citations

Show all 27 references

Sorted by citations

Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association
Benjamin, E. J., Muntner, P., Alonso, A., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Das, S. R., et al. (2019) · Circulation · doi:10.1161/cir.0000000000000659 · Cited by 9,036
Heart disease and stroke statistics-2018 update: a report from the american heart association
Benjamin, E. J., Virani, S. S., Callaway, C. W., Chamberlain, A. M., Chang, A. R., Cheng, S., Chiuve, S. E., Cushman, M., Delling, F. N., Deo, R., et al. (2018) · Circulation · doi:10.1161/cir.0000000000000558 · Cited by 7,146
Membrane transporters in drug development
The International Transporter Consortium, Giacomini, K. M., Huang, S.-M., Tweedie, D. J., Benet, L. Z., Brouwer, K. L. R., Chu, X., Dahlin, A., Evers, R., Fischer, V., et al. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3028 · Cited by 3,340
Guidelines for the Primary Prevention of Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association
Meschia, J. F., Bushnell, C., Boden-Albala, B., Braun, L. T., Bravata, D. M., Chaturvedi, S., Creager, M. A., Eckel, R. H., Elkind, M. S. V., Fornage, M., et al. (2014) · Stroke · doi:10.1161/str.0000000000000046 · Cited by 2,650
The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial
Baigent, C., Landray, M. J., Reith, C., Emberson, J., Wheeler, D. C., Tomson, C., Wanner, C., Krane, V., Cass, A., Craig, J., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60739-3 · Cited by 2,479
Benefits and limitations of genome-wide association studies
Tam, V., Patel, N. K., Turcotte, M., Bossé, Y., Paré, G., & Meyre, D. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0127-1 · Cited by 2,208
Interpretation of the evidence for the efficacy and safety of statin therapy
Collins, R., Reith, C., Emberson, J., Armitage, J., Baigent, C., Blackwell, L., Blumenthal, R., Danesh, J., Smith, G. D., DeMets, D., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31357-5 · Cited by 1,857
Genomewide Association Studies and Assessment of the Risk of Disease
Manolio, T. A. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0905980 · Cited by 1,512
Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management
Stroes, E. S., Thompson, P. D., Corsini, A., Vladutiu, G. D., Raal, F. J., Ray, K. K., Roden, M., Stein, E., Tokgözoğlu, L., Nordestgaard, B. G., et al. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv043 · Cited by 1,443
KDOQI clinical practice guideline for diabetes and CKD: 2012 update
(2012) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2012.07.005 · Cited by 1,320
“Higher doses of lipid lowering medicines, however, are associated with increased risk of myopathy,(89) particularly among patients with reduced kidney function.(90) Therefore, doses of some lipid-lowering medicines should be modified in moderate–to-advanced CKD (stages 3-5).”
Background
Guidelines for the Primary Prevention of Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association
Goldstein, L. B., Bushnell, C. D., Adams, R. J., Appel, L. J., Braun, L. T., Chaturvedi, S., Creager, M. A., Culebras, A., Eckel, R. H., Hart, R. G., et al. (2011) · Stroke · doi:10.1161/str.0b013e3181fcb238 · Cited by 1,306
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., et al. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1078-5 · Cited by 1,280
“Notably, the genetic variant OATP1B1*5 has been shown to be significantly associated with a higher risk for statin-induced myopathy (Link et al. 2008).”
Uncovering the roles of rare variants in common disease through whole-genome sequencing
Cirulli, E. T., & Goldstein, D. B. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2779 · Cited by 1,136
Human genetic variation and its contribution to complex traits
Frazer, K. A., Murray, S. S., Schork, N. J., & Topol, E. J. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2554 · Cited by 1,073
Human metabolic individuality in biomedical and pharmaceutical research
CARDIoGRAM, Suhre, K., Shin, S.-Y., Petersen, A.-K., Mohney, R. P., Meredith, D., Wägele, B., Altmaier, E., Deloukas, P., Erdmann, J., et al. (2011) · Nature · doi:10.1038/nature10354 · Cited by 1,017
Impact of OATP transporters on pharmacokinetics
Kalliokoski, A., & Niemi, M. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00430.x · Cited by 994
“The most convincing data on the clinical significance of the SLCO1B1 polymorphism comes from a recent genome-wide association study investigating simvastatin-induced myopathy (Link et al., 2008).”
Background
Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation
Klaassen, C. D., & Aleksunes, L. M. (2010) · Pharmacological Reviews · doi:10.1124/pr.109.002014 · Cited by 818
Statin Toxicity
Ward, N. C., Watts, G. F., & Eckel, R. H. (2019) · Circulation Research · doi:10.1161/circresaha.118.312782 · Cited by 799
Guidelines for the Primary Prevention of Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.
Goldstein, L. B., Bushnell, C., Adams, R. J., Appel, L. J., Braun, L. T., Chaturvedi, S., Creager, M. A., Culebras, A., Eckel, R. H., Hart, R. G., et al. (2011) · Stroke · Cited by 745
Statin-Associated Side Effects
Thompson, P. D., Panza, G. A., Zaleski, A. L., & Taylor, B. A. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.02.071 · Cited by 775
Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association
Newman, C. B., Preiss, D., Tobert, J. A., Jacobson, T. A., Page, R. L., II, Goldstein, L. B., Chin, C. C., Tannock, L. R., Miller, M. J., Raghuveer, G., et al. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atv.0000000000000073 · Cited by 790
“However, results from the SEARCH RCT did suggest that CKD was a risk factor for simvastatin 80 mg/d.(53) To decrease the risk of myopathy, there are maximum dose recommendations for several statins when used in patients with renal impairment (Table 2).”
BackgroundResultInfluential
The pharmacology of statins
Sirtori, C. R. (2014) · Pharmacological Research · doi:10.1016/j.phrs.2014.03.002 · Cited by 753
Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy
Mammen, A. L., Chung, T., Christopher‐Stine, L., Rosen, P., Rosen, A., Maurer, K. D., & Casciola-Rosen, L. A. (2010) · Arthritis & Rheumatism · doi:10.1002/art.30156 · Cited by 694
Clinical assessment incorporating a personal genome
Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60452-7 · Cited by 674
HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment
HPS2-THRIVE Collaborative Group, Haynes, R., Jiang, L., Hopewell, J. C., Li, J., Chen, F., Parish, S., Landray, M. J., Collins, R., Armitage, J., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht055 · Cited by 676
Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake
Niemi, M., Pasanen, M. K., & Neuvonen, P. J. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.002857 · Cited by 639
224th ENMC International Workshop:
Allenbach, Y., Mammen, A. L., Benvéniste, O., Stenzel, W., Allenbach, Y., Amato, A. A., Aussey, A., Benvéniste, O., Bleecker, J. D., de Groot, I., et al. (2017) · Neuromuscular Disorders · doi:10.1016/j.nmd.2017.09.016 · Cited by 586
Dyslipidemia
Kopin, L., & Lowenstein, C. J. (2017) · Annals of Internal Medicine · doi:10.7326/aitc201712050 · Cited by 610
Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects
König, J., Müller, F., & Fromm, M. F. (2013) · Pharmacological Reviews · doi:10.1124/pr.113.007518 · Cited by 595
Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism
Golomb, B. A., & Evans, M. A. (2008) · American Journal of Cardiovascular Drugs · doi:10.2165/0129784-200808060-00004 · Cited by 677
Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group (2010) · The Lancet · doi:10.1016/s0140-6736(10)60310-8 · Cited by 558
Anti-PCSK9 Antibody Effectively Lowers Cholesterol in Patients With Statin Intolerance
Stroes, E., Colquhoun, D., Sullivan, D., Civeira, F., Rosenson, R. S., Watts, G. F., Bruckert, E., Cho, L., Dent, R., Knusel, B., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.03.019 · Cited by 526
“Lipoprotein(a), nmol/l 57 (22, 205) 39 (10, 101) 26 (7, 181) 31 (9, 80) Apolipoprotein A-I, mg/dl 154 34 149 29 144 23 153 24”
BackgroundInfluential
What do drug transporters really do?
Nigám, S. K. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4461 · Cited by 547
The SLCO1B1*5Genetic Variant Is Associated With Statin-Induced Side Effects
Voora, D., Shah, S. H., Spasojević, I., Ali, S. Y., Reed, C. R., Salisbury, B. A., & Ginsburg, G. S. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.04.053 · Cited by 500
An assessment by the statin muscle safety task force: 2014 update
Rosenson, R. S., Baker, S. K., Jacobson, T. A., Kopecky, S. L., & Parker, B. A. (2014) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2014.03.004 · Cited by 485
Bayesian statistical methods for genetic association studies
Stephens, M., & Balding, D. J. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2615 · Cited by 480
Pharmacogenetics, Pharmacogenomics, and Individualized Medicine
Ma, Q., & Lu, A. Y. H. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.003533 · Cited by 466
“…of genetic testing can indeed benefit the selection of appropriate therapeutic agent and drug dose for individual patients to improve therapeutic response, reduce adverse drug effects, and reduce overall healthcare cost are critical for wide clinical acceptance of pharmacogenetic testing.”
Background
Narrative review: statin-related myopathy
Joy, T. R., & Hegele, R. A. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-150-12-200906160-00009 · Cited by 453
“Recently, a common DNA polymorphism in the SLCO1B1 gene encoding organic anion-transporting polypeptide was strongly associated with simvastatin-associated myopathy (55), but this association was not seen in patients with atorvastatinassociated myopathy (59).”
Background
Pharmacogenomics
Roden, D. M., McLeod, H. L., Relling, M. V., Williams, M. S., Mensah, G. A., Peterson, J. F., & Driest, S. L. V. (2019) · The Lancet · doi:10.1016/s0140-6736(19)31276-0 · Cited by 455
The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update
Ramsey, L. B., Johnson, S. G., Caudle, K. E., Haidar, C. E., Voora, D., Wilke, R. A., Maxwell, W. D., McLeod, H. L., Krauss, R. M., Roden, D. M., et al. (2014) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2014.125 · Cited by 444
ABCG2 Polymorphism Markedly Affects the Pharmacokinetics of Atorvastatin and Rosuvastatin
Keskitalo, J. E., Zolk, O., Fromm, M. F., Kurkinen, K. J., Neuvonen, P. J., & Niemi, M. (2009) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2009.79 · Cited by 417
Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Russmann, S., Kullak-Ublick, G. A., & Grattagliano, I. (2009) · Current Medicinal Chemistry · doi:10.2174/092986709788803097 · Cited by 412
“Genome wide association studies that analyze several hundred thousand single nucleotide polymorphisms (SNPs) per patient have now become technically and economically feasible and have been successfully used for the identification of genetic risk factors even of rare adverse drug reactions in large phase III clinical t…”
Method
SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid
Tornio, A., Vakkilainen, J., Neuvonen, M., Backman, J. T., Neuvonen, P. J., & Niemi, M. (2015) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0000000000000148 · Cited by 409
Personalized Medicine: Progress and Promise
Chan, I. S., & Ginsburg, G. S. (2011) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082410-101446 · Cited by 409
The SLCO (former SLC21) superfamily of transporters
Hagenbuch, B., & Stieger, B. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.10.009 · Cited by 399
“This is exemplified in the case of SLCO1B1, which in an elegant genome-wide association study was associated with simvastatin-induced myotoxicity (Link et al., 2008).”
Background
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver
van de Steeg, E., Stránecký, V., Hartmannová, H., Nosková, L., Hřebı́ček, M., Wagenaar, E., van Esch, A., de Waart, D. R., Elferink, R. P. J. O., Kenworthy, K. E., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59526 · Cited by 379
Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine
Ahmed, S., Zhou, Z. M., Zhou, J., & Chen, S. (2016) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2016.03.008 · Cited by 417
Classification of Inhibitors of Hepatic Organic Anion Transporting Polypeptides (OATPs): Influence of Protein Expression on Drug–Drug Interactions
Karlgren, M., Vildhede, A. M., Norinder, U., Wiśniewski, J. R., Kimoto, E., Lai, Y., Haglund, U., & Artursson, P. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300212s · Cited by 375
Statin-Associated Autoimmune Myopathy
Mammen, A. L. (2016) · New England Journal of Medicine · doi:10.1056/nejmra1515161 · Cited by 366
The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 , ABCG2 , and CYP2C9 genotypes and Statin‐Associated Musculoskeletal Symptoms
Cooper‐DeHoff, R. M., Niemi, M., Ramsey, L. B., Luzum, J. A., Tarkiainen, E. K., Straka, R. J., Gong, L., Tuteja, S., Wilke, R. A., Wadelius, M., et al. (2022) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2557 · Cited by 366
Emerging Role of Precision Medicine in Cardiovascular Disease
Leopold, J. A., & Loscalzo, J. (2018) · Circulation Research · doi:10.1161/circresaha.117.310782 · Cited by 380
Drug Transporters in Drug Efficacy and Toxicity
DeGorter, M. K., Xia, C. Q., Yang, J. J., & Kim, R. B. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134529 · Cited by 372
“521T>C to be the single best predictor of myopathy risk in individuals on high doses of simvastatin (124).”
Background
Quality Control Procedures for Genome‐Wide Association Studies
Turner, S., Armstrong, L. L., Bradford, Y., Carlson, C. S., Crawford, D. C., Crenshaw, A., de Andrade, M., Doheny, K. F., Haines, J. L., Hayes, M. G., et al. (2011) · Current Protocols in Human Genetics · doi:10.1002/0471142905.hg0119s68 · Cited by 373
“More recently, GWAS are being conducted in cohorts that are clinic-based (Link et al., 2008; Daly et al., 2009; Thompson et al., 2009; Barber et al., 2010).”
Background
Bringing genome-wide association findings into clinical use
Manolio, T. A. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3523 · Cited by 362
Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans
Watanabe, T., Kusuhara, H., Maeda, K., Shitara, Y., & Sugiyama, Y. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.146647 · Cited by 351
“…myopathy after receiving pravastatin or atorvastatin (which is also an OATP1B1 substrate) than in patients without myopathy, and a genome-wide study elucidated that the variants in OATP1B1 are strongly associated with an increased risk of simvastatin-induced myopathy (Link et al., 2008).”
Background
Immune‐mediated necrotizing myopathy associated with statins
Grable-Esposito, P., Katzberg, H. D., Greenberg, S. A., Srinivasan, J., Katz, J., & Amato, A. A. (2009) · Muscle & Nerve · doi:10.1002/mus.21486 · Cited by 340
Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials
(2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(16)30156-5 · Cited by 338
Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis
Abraldes, J. G., Villanueva, C., Aracil, C., Turnes, J., Hernandez-Guerra, M., Genesca, J., Rodriguez, M., Castellote, J., García-Pagán, J. C., Torres, F., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.01.004 · Cited by 339
Epidemiology, epigenetics and the ‘Gloomy Prospect’: embracing randomness in population health research and practice
Smith, G. D. (2011) · International Journal of Epidemiology · doi:10.1093/ije/dyr117 · Cited by 339
Influence of the microbiome, diet and genetics on inter-individual variation in the human plasma metabolome
Chen, L., Zhernakova, D. V., Kurilshikov, A., Andreu-Sánchez, S., Wang, D., Augustijn, H. E., Vich Vila, A., Study, L. C., Weersma, R. K., Medema, M. H., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-02014-8 · Cited by 327
The Clinical Pharmacogenomics Implementation Consortium: CPIC Guideline for SLCO1B1 and Simvastatin-Induced Myopathy
Wilke, R. A., Ramsey, L. B., Johnson, S. G., Maxwell, W. D., McLeod, H. L., Voora, D., Krauss, R. M., Roden, D. M., Feng, Q., Cooper‐DeHoff, R. M., et al. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.57 · Cited by 333
Transporter Pharmacogenetics and Statin Toxicity
Niemi, M. (2009) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2009.197 · Cited by 329
Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS)
Varma, M. V., Steyn, S. J., Allerton, C., & El-Kattan, A. F. (2015) · Pharmaceutical Research · doi:10.1007/s11095-015-1749-4 · Cited by 334
Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study
Nielsen, S. F., & Nordestgaard, B. G. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv641 · Cited by 329
Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features
Cervellin, G., Comelli, I., & Lippi, G. (2010) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2010.151 · Cited by 323
Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy
Ross, C. J., Katzov-Eckert, H., Dubé, M., Brooks, B., Rassekh, S. R., Barhdadi, A., Zada, Y. F., Visscher, H., Brown, A. M. K., Rieder, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.478 · Cited by 326
A Genome-wide Association Study of the Human Metabolome in a Community-Based Cohort
Rhee, E. P., Ho, J. E., Chen, M., Shen, D., Cheng, S. C., Larson, M. G., Ghorbani, A., Shi, X. D., Helenius, I. T., O’Donnell, C. J., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.013 · Cited by 318
“, 2012); at SLCO1B1 (solute carrier organic anion transporter family member 1B1), associated with LPE 20:4, has been associated with statin-induced myopathy (Link et al., 2008); and at PDE4D (phosphodiesterase 4D), associated with SM 24:1, has previously been linked to stroke (Song et al.”
Influential
Statin-induced myopathy: a review and update
Abd, T. T., & Jacobson, T. A. (2011) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2011.540568 · Cited by 320
“Multiple studies have shown an association between SLCO1B1 polymorphisms and statin myopathy [40,41].”
BackgroundMethod
Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022
Okamura, T., Tsukamoto, K., Arai, H., Fujioka, Y., Ishigaki, Y., Koba, S., Ohmura, H., Shoji, T., Yokote, K., Yoshida, H., et al. (2023) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.gl2022 · Cited by 323
A large electronic-health-record-based genome-wide study of serum lipids
Hoffmann, T. J., Theusch, E., Haldar, T., Ranatunga, D. K., Jorgenson, E., Medina, M. W., Kvale, M. N., Kwok, P., Schaefer, C. A., Krauss, R. M., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0064-5 · Cited by 291
Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial
Chasman, D. I., Giulianini, F., MacFadyen, J., Barratt, B. J., Nyberg, F., & Ridker, P. M. (2012) · Circulation: Cardiovascular Genetics · doi:10.1161/circgenetics.111.961144 · Cited by 285
Pathogenesis of cholestatic liver disease and therapeutic approaches
Hirschfield, G. M., Heathcote, E. J., & Gershwin, M. E. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.09.004 · Cited by 287
Genomics of Cardiovascular Disease
O’Donnell, C. J., & Nabel, E. G. (2011) · New England Journal of Medicine · doi:10.1056/nejmra1105239 · Cited by 287
The neurobiology of individual differences in complex behavioral traits
Hariri, A. R. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.051508.135335 · Cited by 273
“…efficient high-throughput identification of such variation in individuals have dramatically accelerated the discovery of genes involved in the emergence of complex disease processes (Fellay et al. 2007, Link et al. 2008) as well as normal variability in continuous traits (Lettre et al. 2008).”
Background
Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients: A Randomized Trial
Becker, D. J., Gordon, R. Y., Halbert, S. C., French, B., Morris, P. B., & Rader, D. J. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-150-12-200906160-00006 · Cited by 275
“A recent study showed that patients with variants in the SLCO1B1 gene were more likely to develop statin-associated myopathy with higher doses of simvastatin (31).”
Background
The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation
Stieger, B. (2010) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-14541-4_5 · Cited by 277
Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins
Postmus, I., Trompet, S., Deshmukh, H., Barnes, M. R., Li, X., Warren, H. R., Chasman, D. I., Zhou, K., Arsenault, B. J., Donnelly, L. A., et al. (2014) · Nature Communications · doi:10.1038/ncomms6068 · Cited by 268
Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial
Topol, E. J., Bousser, M.-G., Fox, K. A., Creager, M. A., Despres, J.-P., Easton, J. D., Hamm, C. W., Montalescot, G., Steg, P. G., Pearson, T. A., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60935-x · Cited by 266
Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1
Nies, A. T., Niemi, M., Burk, O., Winter, S., Zanger, U. M., Stieger, B., Schwab, M. G., & Schaeffeler, E. (2013) · Genome Medicine · doi:10.1186/gm405 · Cited by 273
Genome-wide association studies in pharmacogenomics
Daly, A. K. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2751 · Cited by 264
Comprehensive Pharmacogenetic Analysis of Irinotecan Neutropenia and Pharmacokinetics
Innocenti, F., Kroetz, D. L., Schuetz, E. G., Dolan, M. E., Ramı́rez, J., Relling, M. V., Chen, P., Das, S., Rosner, G. L., & Ratain, M. J. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.20.6300 · Cited by 264
PharmGKB summary
Scott, S. A., Sangkuhl, K., Shuldiner, A. R., Hulot, J., Thorn, C. F., Altman, R. B., & Klein, T. E. (2011) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32834d4962 · Cited by 262
Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate dispositionPreprint
Ramsey, L. B., Bruun, G. H., Yang, W., Treviño, L. R., Vattathil, S., Scheet, P. A., Cheng, C., Rosner, G. L., Giacomini, K. M., Fan, Y., et al. (2011) · Genome Research · doi:10.1101/gr.129668.111 · Cited by 266
Pharmacogenomics and Individualized Medicine: Translating Science Into Practice
Crews, K. R., Hicks, J. K., Pui, C.-H., Relling, M. V., & Evans, W. E. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.120 · Cited by 255
Predictors of statin adherence, switching, and discontinuation in the USAGE survey: Understanding the use of statins in America and gaps in patient education
Wei, M. Y., Ito, M. K., Cohen, J. D., Brinton, E. A., & Jacobson, T. A. (2013) · Journal of clinical lipidology · doi:10.1016/j.jacl.2013.03.001 · Cited by 260
A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation
Coviello, A. D., Haring, R., Wellons, M., Vaidya, D., Lehtimäki, T., Keildson, S., Lunetta, K. L., He, C., Fornage, M., Lagou, V., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002805 · Cited by 250
“1-SLCO1B1 [ 76 ], 15q26.”
Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016)
Mancini, G. B. J., Baker, S. K., Bergeron, J., FITCHETT, D. H., Frohlich, J. J., Genest, J. J., Gupta, M., Hegele, R. A., Ng, D. S., Pearson, G. J., et al. (2016) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2016.01.003 · Cited by 257
Pharmacogenomics: Precision Medicine and Drug Response
Weinshilboum, R. M., & Wang, L. (2017) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2017.09.001 · Cited by 269
Diagnostic evaluation of rhabdomyolysis
Nance, J., & Mammen, A. L. (2015) · Muscle & Nerve · doi:10.1002/mus.24606 · Cited by 244
“Of note, the risk of statin-triggered myopathy is particularly increased in patients with a single-nucleotide polymorphism located within the SLCO1B1 gene, which encodes a transport protein involved in regulation of hepatic statin uptake.(59)”
Background
Genome-wide association meta-analysis for total serum bilirubin levels
Johnson, A. D., Kavousi, M., Smith, A. V., Chen, M., Dehghan, A., Aspelund, T., Lin, J.-P., van Duijn, C. M., Harris, T. B., Cupples, L. A., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp202 · Cited by 235
The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 236
Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response
Kozyra, M., Ingelman‐Sundberg, M., & Lauschke, V. M. (2016) · Genetics in Medicine · doi:10.1038/gim.2016.33 · Cited by 230
Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition
Schirris, T. J. J., Renkema, G. H., Ritschel, T., Voermans, N. C., Bilos, A., van Engelen, B. G. M., Brandt, U., Koopman, W. J. H., Beyrath, J., Rodenburg, R. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.08.002 · Cited by 235
“…the association of statin-induced myopathies with several genetic polymorphisms in various drug transporters, autophagy clearance pathways, and enzymes involved in creatine synthesis (Mangravite et al., 2013; Needham and Mastaglia, 2014; Link et al., 2008; Zeharia et al., 2008; Zhang et al., 2014).”
A statin-dependent QTL for GATM expression is associated with statin-induced myopathy
Mangravite, L. M., Engelhardt, B. E., Medina, M. W., Smith, J. D., Brown, C. D., Chasman, D. I., Mecham, B. H., Howie, B., Shim, H., Naidoo, D., et al. (2013) · Nature · doi:10.1038/nature12508 · Cited by 224
In vitro-in vivo Extrapolation of Transporter-mediated Clearance in the Liver and Kidney
Kusuhara, H., & Sugiyama, Y. (2009) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.24.37 · Cited by 221
Human skeletal muscle drug transporters determine local exposure and toxicity of statins
Knauer, M. J., Urquhart, B. L., Meyer zu Schwabedissen, H. E., Schwarz, U. I., Lemke, C. J., Leake, B. F., Kim, R. B., & Tirona, R. G. (2010) · Circulation Research · doi:10.1161/circresaha.109.203596 · Cited by 222
Pharmacogenomics
Roden, D. M., Wilke, R. A., Kroemer, H. K., & Stein, C. M. (2011) · Circulation · doi:10.1161/circulationaha.109.914820 · Cited by 222
SLC Family Transporters
Liu, X. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-7647-4_3 · Cited by 231
Phenotype standardization for statin-induced myotoxicity
Alfirevic, A., Neely, D., Armitage, J., Chinoy, H., Cooper, R. G., Laaksonen, R., Carr, D. F., Bloch, K. M., Fahy, J., Hanson, A., et al. (2014) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2014.121 · Cited by 220
Mutations in LPIN1 Cause Recurrent Acute Myoglobinuria in Childhood
Zeharia, A., Shaag, A., Houtkooper, R. H., Hindi, T., de Lonlay, P., Erez, G., Hubert, L., Saada, A., de Keyzer, Y., Eshel, G. M., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.09.002 · Cited by 219

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
DOI: 10.1056/nejmoa0801936
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks