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 = 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.)
| Original language | English (US) |
|---|---|
| Pages (from-to) | 789-799 |
| Number of pages | 11 |
| Journal | New England Journal of Medicine |
| Volume | 359 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 21 2008 |
| Externally published | Yes |
ASJC Scopus subject areas
- General Medicine
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In: New England Journal of Medicine, Vol. 359, No. 8, 21.08.2008, p. 789-799.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - SLCO1B1 variants and statin-induced myopathy - A genomewide study
AU - Meade, T.
AU - Sleight, P.
AU - Collins, R.
AU - Armitage, J.
AU - Parish, S.
AU - Barton, J.
AU - Bray, C.
AU - Wincott, E.
AU - Bowman, L.
AU - Clarke, R.
AU - Graham, I.
AU - Simpson, D.
AU - Warlow, C.
AU - Wilcken, D.
AU - Tobert, J.
AU - Musliner, T.
AU - Wilhelmsen, L.
AU - Doll, R.
AU - Fox, K. M.
AU - Hill, C.
AU - Sandercock, P.
AU - Peto, R.
AU - Webster, J.
AU - Jamieson, J.
AU - Nixon, A.
AU - Lackie, S.
AU - Thompson, J.
AU - Brown, M.
AU - Blackwood, S.
AU - Morgan, M.
AU - Rhoden, W.
AU - Saeed, B.
AU - Houghton, M.
AU - Nicholson, A.
AU - Simpson, C.
AU - Hoburn, B.
AU - Cooper, I.
AU - Gallivan, A.
AU - Pickerell, E.
AU - Hancock, J.
AU - Watkinson, J.
AU - Ryder, B.
AU - Jones, S.
AU - Burbridge, W.
AU - Kitchen, M.
AU - O'Leary, H.
AU - Verow, C.
AU - Meynell, L.
AU - Rollinson, L.
AU - Bain, S.
AU - Jones, A.
AU - Jewkes, C.
AU - Russon, C.
AU - Bateson, M.
AU - Gill, P.
AU - Nicol, J.
AU - Stansbie, D.
AU - Bayly, G.
AU - Andrews, G.
AU - Halestrap, M.
AU - Meredith, J.
AU - Best, R.
AU - Appleyard, D.
AU - Briggs, R.
AU - Wareing, H.
AU - Holmes, K.
AU - Holt, J.
AU - Kenyon, M.
AU - White, C.
AU - Khalifa, M.
AU - Newton, D.
AU - Wass, A.
AU - Watkinson, R.
AU - Creamer, J.
AU - Anderson, S.
AU - Bethell, A.
AU - Butler, C.
AU - Washington, M.
AU - Weston, E.
AU - Machin, J.
AU - Cleaver, K.
AU - Wray, R.
AU - Sinclair, J.
AU - Van Aalst, A.
AU - Been, M.
AU - Mattu, R.
AU - Bates, D.
AU - Burke, A.
AU - Gill, L.
AU - Walton, E.
AU - Cowley, M.
AU - Robson, H.
AU - Graham, A.
AU - Rose, G.
AU - Kerr, M.
AU - Mallinson, J.
AU - Peascod, B.
AU - Kalk, J.
AU - Scott, A.
AU - Donnelly, R.
AU - Gibson, T.
AU - Hannah, J.
AU - Henshaw, L.
AU - Margetts, M.
AU - Pearson, N.
AU - Frost, S.
AU - Murray, S.
AU - Marshall, A.
AU - Went, J.
AU - Inman, A.
AU - Simmonds, J.
AU - Teasdale, A.
AU - Kemp, T.
AU - Roberts, G.
AU - Kooner, J.
AU - Cahill, S.
AU - Lloyd, M.
AU - Molloy, O.
AU - Wrigley, J.
AU - Galvin, M.
AU - Wilder, C.
AU - Swainson, C.
AU - Lindley, R.
AU - Shaw, S.
AU - Hillis, L.
AU - Johnston, J.
AU - Miller, D.
AU - Kennedy, M.
AU - Mushahwar, S.
AU - Savage, M.
AU - Ayer, G.
AU - Schofield, J.
AU - Greenhalgh, S.
AU - Parks, J.
AU - Speak, S.
AU - Coulson, C.
AU - Papouchado, M.
AU - Carpenter, R.
AU - Wisby, J.
AU - Cobbe, S.
AU - Campbell, C.
AU - Hunter, J.
AU - Young, H.
AU - Gallacher, M.
AU - Lindsay, D.
AU - Halliday, A.
AU - Godfrey, S.
AU - O'Donahoo, L.
AU - Chambers, J.
AU - Wierzbicki, A.
AU - Parkin, D.
AU - Nwafor, K.
AU - Vallance, B.
AU - Oldroyd, K.
AU - Cunningham, N.
AU - Moreland, G.
AU - Oldroyd, C.
AU - Crawford, M.
AU - Hillson, R.
AU - Knott, K.
AU - Mahabir, N.
AU - Crouch, A.
AU - MacDonald, Y.
AU - Green, J.
AU - Brown, L.
AU - Heron, J.
AU - Jones, N.
AU - Roberts, M.
AU - Hainsworth, D.
AU - Williams, J.
AU - Barnes, P.
AU - Longworth, C.
AU - Davidson, J.
AU - Irvine, N.
AU - Oliver, R.
AU - Pond, C.
AU - Nuttall, M.
AU - Lloyd-Mostyn, R.
AU - Blackburn, S.
AU - Furnell, W.
AU - Webster, S.
AU - Wheatley, L.
AU - Hudson, I.
AU - Pohl, J.
AU - Nicholson, S.
AU - Mallya, S.
AU - Nash, M.
AU - Spruce, J.
AU - Searle, A.
AU - Bonner, A.
AU - Leather, J.
AU - Davies, E.
AU - Egdell, R.
AU - Price, B.
AU - Robinson, A.
AU - Horton, S.
AU - Cunnington, A.
AU - Giles, P.
AU - Sidaway, J.
AU - Tomlinson, L.
AU - Hawkins, L.
AU - Long, J.
AU - Murphy, J.
AU - Brennan, G.
AU - Boon, M.
AU - Cassidy, S.
AU - Rodger, C.
AU - McNeilly, A.
AU - Radcliffe, A.
AU - Farrer, M.
AU - Bluett, J.
AU - Cowell, L.
AU - Farrell, A.
AU - Gilroy, S.
AU - Warren, S.
AU - MacConnell, T.
AU - Burtchaell, S.
AU - Williams, L.
AU - Rylance, P.
AU - Hodgson, A.
AU - Kertland-Hill, K.
AU - Robinson, L.
AU - Smallwood, A.
AU - Lomas, S.
AU - Ball, J.
AU - Hardy, K.
AU - Benbow, S.
AU - Gerrard, M.
AU - Langley, C.
AU - Fagan, C.
AU - Green, B.
AU - Pringle, T.
AU - Hanna, H.
AU - Mackintosh, A.
AU - Watson, E.
AU - Swan, J.
AU - McSorland, D.
AU - Thompson, G.
AU - O'Neill, C.
AU - Curless, R.
AU - Doig, C.
AU - McKenna, P.
AU - Martin, J.
AU - Murdy, J.
AU - Martin, S.
AU - Birkhead, J.
AU - O'Donnell, J.
AU - Dixon, S.
AU - Hassall, A.
AU - Tanqueray, E.
AU - Vass, D.
AU - Cosford, I.
AU - Elderkin, M.
AU - McKenzie, P.
AU - Gray, T.
AU - Holmshaw, N.
AU - McKinnon, A.
AU - Ali, I.
AU - Stephens, N.
AU - Banfield, A.
AU - Chester, L.
AU - Wiseman, J.
AU - Harrisingh, N.
AU - Patel, R.
AU - Thaker, P.
AU - Watkins, H.
AU - Beebe, S.
AU - Fitzgerald, J.
AU - Godden, J.
AU - Lawson, A.
AU - Lochhead, H.
AU - Taylor, A.
AU - Turner, S.
AU - Rowlands, D.
AU - Cooper, A.
AU - Graham, J.
AU - Hennessy, S.
AU - Rashid, T.
AU - Smith, C.
AU - Nyman, C.
AU - Adams, J.
AU - Hardwick, A.
AU - Buck, P.
AU - Pattinson, C.
AU - Trigg, J.
AU - McLeod, A.
AU - Gardner, S.
AU - Haimes, L.
AU - Orr, S.
AU - Johns, S.
AU - Capps, N.
AU - Cook, A.
AU - Donaldson, D.
AU - Keighley, C.
AU - Stiles, C.
AU - Asbridge, S.
AU - Buller, N.
AU - Hooks, J.
AU - Jones, H.
AU - Watson, R.
AU - Salt, P.
AU - Francis, M.
AU - MacLeod, D.
AU - Allcoat, P.
AU - Stuart, R.
AU - Reynolds, T.
AU - Maiden, J.
AU - Reynolds, J.
AU - Murray, D.
AU - MacFadyen, R.
AU - Potts, L.
AU - Smith, A.
AU - King, L.
AU - Muthusamy, R.
AU - Jones, M.
AU - Lawan, M.
AU - Weston, C.
AU - Nixon, J.
AU - Wasnidge, L.
AU - Hutchesson, A.
AU - Evans, J.
AU - Morris, K.
AU - Oultram, M.
AU - Armitage, M.
AU - Skule, R.
AU - Cope, C.
AU - Page, M.
AU - Fleming, S.
AU - Andain, K.
AU - Parrett, M.
AU - Soper, R.
AU - MacLeod, K.
AU - Gordon, K.
AU - Green, E.
AU - Havill, S.
AU - Stewart, V.
AU - Allen, S.
AU - Henson, S.
AU - Rimmer, C.
AU - Davies, J.
AU - Javed, M.
AU - Norris, A.
AU - Williams, M.
AU - Khan, S.
AU - Dobie, G.
AU - Fitton, J.
AU - Gilbert, S.
AU - Davenport, C.
AU - Williamson, M.
AU - Vincent, R.
AU - Joyce, E.
AU - Reckless, J.
AU - Bishop, A.
AU - Brice, L.
AU - Field, P.
AU - Shute, C.
AU - Stacey, D.
AU - Findlay, I.
AU - Labib, M.
AU - Beddoe, L.
AU - Reed, J.
AU - Barron, J.
AU - Odemuyiwa, O.
AU - Bradford, B.
AU - McDonnell, M.
AU - West, L.
AU - Beck, P.
AU - Gilbey, S.
AU - Clarkson, A.
AU - Drury, K.
AU - Hall, S.
AU - Quartey, D.
AU - Whittam, B.
AU - Lund, D.
AU - Stott, L.
AU - Griffiths, H.
AU - Kudarenko, A.
AU - Watkins, J.
AU - Golledge, S.
AU - Pottle, J.
AU - Little, S.
AU - Paine, B.
AU - Shears, C.
AU - Baxter, M.
AU - Wilkinson, P.
AU - Chambers, R.
AU - Hamper, C.
AU - Hollister, E.
AU - Ramsay, H.
AU - Barber, J.
AU - Hopkins, T.
AU - Hughes, L.
AU - Elson-Whittaker, J.
AU - Lambley, R.
AU - Lloyd, C.
AU - Dhawan, J.
AU - John, J.
AU - Bramley, D.
AU - Catchpole, A.
AU - Colecchia, A.
AU - LeQuelenec, M.
AU - Remington, D.
AU - Gray, C.
AU - Anderson, P.
AU - Woolass, R.
AU - Thomas, P.
AU - Guy, F.
AU - Lynch, J.
AU - Thomas, R.
AU - Coates, S.
AU - Gait, M.
AU - Waller, D.
AU - Elkins, K.
AU - Franklin, M.
AU - Moore, L.
AU - Signy, M.
AU - Chilton, R.
AU - Wrapson, C.
AU - Wiltshire, C.
AU - Lewis, P.
AU - Curtis, J.
AU - O'Toole, J.
AU - Scanlon, S.
AU - Carey, C.
AU - Dobson, L.
AU - Gould, M.
AU - Mansfield, H.
AU - Ranson, G.
AU - Rodaway, M.
AU - Germon, J.
AU - McDowell, I.
AU - Cockcroft, J.
AU - Field, R.
AU - Whiting, J.
AU - Roberts, D.
AU - Cooper, M.
AU - Davies, C.
AU - Radford, L.
AU - Ward, L.
AU - McAlpine, H.
AU - Dougall, H.
AU - Robertson, L.
AU - Scott, L.
AU - Humphrey, P.
AU - Saminaden, S.
AU - Watling, D.
AU - Owen, L.
AU - Clements, M.
AU - Walker, E.
AU - Atkins, E.
AU - Shaw, T.
AU - MacCallum, H.
AU - Markie, D.
AU - Melville, V.
AU - Adamson, L.
AU - Johnston, A.
AU - Poulkard, E.
AU - Rudden, M.
AU - Hogan, J.
AU - Lie, F.
AU - Badger, V.
AU - Duffy, S.
AU - Mitchell, C.
AU - MacQueen, E.
AU - Baxter, R.
AU - Campbell, S.
AU - McDonald, L.
AU - Wood, H.
AU - Munro, A.
AU - Pycock, C.
AU - Cadwell, J.
AU - Doughty, A.
AU - Harvey, M.
AU - Price, S.
AU - Aldersley, M.
AU - Lock, S.
AU - Pendrey, P.
AU - Boland, A.
AU - Delepine, M.
AU - Gut, I.
AU - Heath, S.
AU - Lathrop, M.
AU - Lechner, D.
AU - Matsuda, F.
AU - Zelenika, D.
AU - Dayanandan, R.
AU - Anderson, C.
AU - Benham, J.
AU - Bojowsky, H.
AU - Booker, V.
AU - Brewer, A.
AU - Brindley, G.
AU - Cobb, L.
AU - Corbett, M.
AU - Crowther, J.
AU - Danesh-Pour, S.
AU - Edmunds, K.
AU - Fortun, A.
AU - Grimsey, T.
AU - Harwood, C.
AU - Haywood, D.
AU - Hope, C.
AU - Jones, R.
AU - Kidney, K.
AU - King, M.
AU - Knight, S.
AU - Lang, H.
AU - Madgwick, Z.
AU - Marsden, C.
AU - Marshall, P.
AU - Matthews, C.
AU - Matthewson, M.
AU - Miller, J.
AU - Moss, B.
AU - Mostefai, Y.
AU - Murphy, K.
AU - Naughten, A.
AU - Pickworth, S.
AU - Radley, A.
AU - Southren, S.
AU - Sutherland, S.
AU - Tong, R.
AU - Umbrath, M.
AU - Baigent, C.
AU - Bulbulia, R.
AU - Dasgupta, T.
AU - Haynes, R.
AU - Landray, M.
AU - Mafham, M.
AU - Majoni, W.
AU - Porter, T.
AU - Rahimi, K.
AU - Reith, C.
AU - Walter, K.
AU - Harding, P.
AU - Lay, M.
AU - Wallendszus, K.
AU - Berry, C.
AU - Bennett, D.
AU - Bettesworth, H.
AU - Booth, J.
AU - Bowes, M.
AU - Bu, Y.
AU - Charles, A.
AU - Cleverley, P.
AU - Cody, A.
AU - Cox, J.
AU - Craig, M.
AU - Emberson, J.
AU - Goodwin, N.
AU - Hopewell, J.
AU - Hurt, C.
AU - Link, E.
AU - McCabe, P.
AU - Munday, A.
AU - Murawska, A.
AU - Offer, A.
AU - Palmer, A.
AU - Prajapati, N.
AU - Tochlin, S.
AU - Young, A.
AU - Clark, S.
AU - Kourellias, K.
AU - Radley, M.
AU - Ambrose, V.
AU - Bradley, M.
AU - Bush, E.
AU - Chavagnon, T.
AU - Chukwurah, B.
AU - Crowley, S.
AU - Dunseath, J.
AU - Emmens, K.
AU - Fletcher, L.
AU - Gordon, J.
AU - Gordon, A.
AU - Hickman, C.
AU - Hill, J.
AU - Ji, M.
AU - Lee, A.
AU - Luker, N.
AU - Norris, S.
AU - Priestley, H.
AU - Sullivan, J.
AU - Taylor, J.
AU - Wintour, J.
AU - Yeung, M.
AU - Youngman, L.
PY - 2008/8/21
Y1 - 2008/8/21
N2 - 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.)
AB - 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.)
UR - http://www.scopus.com/inward/record.url?scp=49949104757&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=49949104757&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa0801936
DO - 10.1056/NEJMoa0801936
M3 - Article
C2 - 18650507
AN - SCOPUS:49949104757
SN - 0028-4793
VL - 359
SP - 789
EP - 799
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 8
ER -