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- Wilhelmsen, Lars, 1932, et al.
(författare)
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SLCO1B1 variants and statin-induced myopathy--a genomewide study.
- 2008
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Ingår i: The New England journal of medicine. - 1533-4406. ; 359:8, s. 789-99
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Tidskriftsartikel (refereegranskat)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.)
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- Bowman, Miles C, et al.
(författare)
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Eye-hand coordination in a sequential target contact task
- 2009
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Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 195:2, s. 273-283
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Tidskriftsartikel (refereegranskat)abstract
- Most object manipulation tasks involve a series of actions demarcated by mechanical contact events, and gaze is typically directed to the locations of these events as the task unfolds. Here, we examined the timing of gaze shifts relative to hand movements in a task in which participants used a handle to contact sequentially five virtual objects located in a horizontal plane. This task was performed both with and without visual feedback of the handle position. We were primarily interested in whether gaze shifts, which in our task shifted from a given object to the next about 100 ms after contact, were predictive or triggered by tactile feedback related to contact. To examine this issue, we included occasional catch contacts where forces simulating contact between the handle and object were removed. In most cases, removing force did not alter the timing of gaze shifts irrespective of whether or not vision of handle position was present. However, in about 30% of the catch contacts, gaze shifts were delayed. This percentage corresponded to the fraction of contacts with force feedback in which gaze shifted more than 130 ms after contact. We conclude that gaze shifts are predictively controlled but timed so that the hand actions around the time of contact are captured in central vision. Furthermore, a mismatch between the expected and actual tactile information related to the contact can lead to a reorganization of gaze behavior for gaze shifts executed greater than 130 ms after a contact event.
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