| 1. |
- Paré, Guillaume, et al.
(författare)
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Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding
- 2013
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 127:13, s. 1404-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in prevention of stroke in atrial fibrillation patients compared to warfarin. We hypothesized that genetic variants could contribute to inter-individual variability in blood concentrations of the active metabolite of dabigatran etexilate, and influence the safety and efficacy of dabigatran.Methods and ResultsWe successfully conducted a genome-wide association study in 2,944 RE-LY participants. The CES1 SNP rs2244613 was associated with trough concentrations, and the ABCB1 SNP rs4148738 and CES1 SNP rs8192935 were associated with peak concentrations at genome-wide significance (P<9 x 10-8) with a gene-dose effect. Each minor allele of the CES1 SNP rs2244613 was associated with lower trough concentrations (15% decrease per allele, 95%CI 10-19%; P=1.2 x 10-8) and a lower risk of any bleeding (OR=0.67, 95%CI 0.55-0.82; P=7 x 10-5) in dabigatran-treated participants, with a consistent but non-significant lower risk of major bleeding (OR=0.66, 95%CI 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002) with carriers having less bleeding with dabigatran than warfarin (HR=0.59, 95%CI 0.46-0.76; P=5.2 x 10-5) in contrast to no difference in noncarriers (HR=0.96, 95%CI 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.ConclusionsGenome-wide association analysis identified that carriage of CES1 rs2244613 minor allele occurred in 32.8% of patients in RELY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.
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| 2. |
- Alfirevic, A., et al.
(författare)
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Phenotype Standardization for Statin-Induced Myotoxicity
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 96:4, s. 470-476
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Forskningsöversikt (refereegranskat)abstract
- Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.
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| 3. |
- Avery, P. J., et al.
(författare)
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A Proposal for an Individualized Pharmacogenetics-Based Warfarin Initiation Dose Regimen for Patients Commencing Anticoagulation Therapy
- 2011
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 90:5, s. 701-706
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)(days 4-7)>4.0 (n = 63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction = 4.2 mg), whereas in those with mean INR(days 4-7) < 2.0 (n = 145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.
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| 4. |
- Becquemont, Laurent, et al.
(författare)
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Practical recommendations for pharmacogenomics-based prescription : 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics
- 2011
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 12:1, s. 113-124
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Forskningsöversikt (refereegranskat)abstract
- The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.
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| 5. |
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| 6. |
- Caudle, Kelly E, et al.
(författare)
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Incorporation of Pharmacogenomics into Routine Clinical Practice : the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process
- 2014
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Ingår i: Current drug metabolism. - : Bentham Science Publishers Ltd.. - 1389-2002 .- 1875-5453. ; 15:2, s. 209-217
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Tidskriftsartikel (refereegranskat)abstract
- The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
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| 7. |
- Cavallari, Larisa H., et al.
(författare)
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Association of the GGCX (CAA) 16/17 repeat polymorphism with higher warfarin dose requirements in African Americans
- 2012
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 22:2, s. 152-158
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Tidskriftsartikel (refereegranskat)abstract
- Objective Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the gamma-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population.Methods A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA) n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5mg/day alone and in the context of other variables known to influence dose variability.Results The GGCX rs10654848 (CAA) 16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P = 0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA) 16 repeat frequency of only 0.27% (P = 0.008 compared with African Americans).Conclusion These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA) 16/17 repeat compared with Caucasians. Pharmacogenetics and Genomics 22: 152-158 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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| 8. |
- Dias, M M, et al.
(författare)
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The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy : a collaborative meta-analysis
- 2014
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Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 14:5, s. 424-431
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Tidskriftsartikel (refereegranskat)abstract
- To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.
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| 9. |
- Eriksson, Niclas, 1978-
(författare)
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On the Prediction of Warfarin Dose
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.
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| 10. |
- Eriksson, Niclas, et al.
(författare)
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Prediction of warfarin dose : why, when and how?
- 2012
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 13:4, s. 429-440
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Forskningsöversikt (refereegranskat)abstract
- Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.
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