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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
SLCO1B1 variants and statin-induced myopathy - A genomewide study
New England Journal of Medicine, Volume 359, No. 8, Year 2008
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Description
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 = 4×10-9). 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 (r2 = 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.) Copyright © 2008 Massachusetts Medical Society.
Authors & Co-Authors
Meade, Thomas W.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Sleight, Peter J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Collins, Rory
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Bray, Christopher M.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Bowman, Louise J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Clarke, Robert Joseph
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Graham, Ian Maklim
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Simpson, David Martin
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Warlow, Charles P.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Wilhelmsen, Lars W.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Doll, Richard S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Hill, Catherine
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Sandercock, Peter A.G.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Peto, Richard R.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Thompson, John R.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Gill, Paramjit Singh
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Andrews, Gavin A.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Burke, Andrew
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Rose, Geofferey Alan
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Kerr, Michael Patrick
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Donnelly, Richard J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Kooner, Jaspal Singh
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Lloyd, Michael Shane
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Lindley, Richard Iain
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Johnston, James Cameron
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Campbell, Christina A.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Wierzbicki, Anthony S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Parkin, Donald Maxwell
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Knott, Kristopher D.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Green, Jane W.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Heron, Jon E.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Jones, Nev
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Roberts, Michael S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Williams, John Lewis
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Barnes, Peter John
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Pond, Constance Dimity
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Bonner, Ashley Joel
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Davies, E. A.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Horton, Sarah C.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Tomlinson, Laurie A.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Hawkins, Lesley
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Brennan, Geraldine M.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
McNeilly, Allan S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Farrer, Matthew J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Williams, Lyn Keoki
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Doig, Christopher James
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Martin, Seth S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Dixon, Simon
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Patel, Rita
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Watkins, Hugh C.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
FitzGerald, J. Mark
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Donaldson, Debra D.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Stuart, Robert K.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
David W. Murray, David W.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Smith, Alexandra G.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Gilbert, Sarah C.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Williamson, Martin S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Stacey, Dawn
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
West, Lori J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Little, Susan J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Barber, John C.K.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Thomas, Rebecca L.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Gould, Michael K.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Roberts, David Hesketh
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Davies, Christina
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Clements, Mark S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Markie, David M.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Hogan, Joseph W.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Price, Susanna
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Boland, Anne
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Délépine, Marc
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Gut, I. Glynne
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Lathrop, Mark G.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Lechner, Doris
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Matsuda, Fumihiko
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Zélénika, Diana
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Anderson, Craig S.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Cobb, Laura K.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Corbett, Mark A.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Harwood, Catherine Anne
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Marshall, Patricia A.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Baigent, Colin
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Landray, Martin J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Majoni, Sandawana William
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Rahimi, Kazem
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Walter, Klaudia
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Harding, Peter J.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Bennett, Derrick A.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Charles, Anthony G.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Hopewell, Jemma C.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Hurt, Chris Nicholas
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Hill, Jennifer L.
United Kingdom, Oxford
Clinical Trial Service Unit and Epidemiological Studies Unit
Statistics
Citations: 1,891
Authors: 92
Affiliations: 1
Identifiers
Doi:
10.1056/NEJMoa0801936
ISSN:
00284793
Research Areas
Genetics And Genomics
Noncommunicable Diseases
Study Design
Cross Sectional Study
Case-Control Study