| 1. |
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| 2. |
- 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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| 3. |
- Cavalli, Marco, et al.
(författare)
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Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate
- 2022
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Ingår i: Pharmacogenomics (London). - : Future Medicine. - 1462-2416 .- 1744-8042. ; 23:15, s. 813-820
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Tidskriftsartikel (refereegranskat)abstract
- Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 × 10-8) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 × ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified.
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| 4. |
- Cavalli, Marco, et al.
(författare)
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Novel regulatory variant detected on the VKORC1 haplotype that is associated with warfarin dose
- 2016
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 17:12, s. 1305-1314
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Warfarin dose requirement is associated with VKORC1 rs9923231, and we studied whether it is a functional variant.Materials & methods: We selected variants in linkage disequilibrium with rs9923231 that bind transcription factors in an allele-specific way. Representative haplotypes were cloned or constructed, nuclear protein binding and transcriptional activity were evaluated.Results: rs56314408C>T and rs2032915C>T were detected in a liver enhancer in linkage disequilibrium with rs9923231. The rs56314408-rs2032915 C-C haplotype preferentially bound nuclear proteins and had higher transcriptional activity than T-T and the African-specific T-C. A motif for TFAP2A/C was disrupted by rs56314408T. No difference in transcriptional activity was detected for rs9923231G>A.Conclusion: Our results supported an activating role for rs56314408C, while rs9923231G>A had no evidence of being functional.
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| 5. |
- Eliasson, E, et al.
(författare)
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Institutional profile: Karolinska Institutet
- 2012
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 13:16, s. 1887-1891
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Tidskriftsartikel (refereegranskat)abstract
- Research in pharmacogenomics has been intensive at Karolinska Institutet (KI) for approximately 25 years. Initial initiatives were focused on the identification and characterization of novel CYP2D6 alleles causing ultrarapid or defective drug metabolism. Such discoveries were possible owing to the early implementation of therapeutic drug monitoring and the access to individuals phenotyped with respect to drug metabolism. The translational work at KI has been of utmost importance for successful research, including functional characterization and clinical validation of allelic variants in drug metabolism, as well as discoveries of novel polymorphisms, recent examples being the CYP2C19 and UGT2B17 genes. The clinical pharmacology laboratory at KI campus Huddinge is one of the leading sites for therapeutic drug monitoring in northern Europe and obtains an increasing number of clinical requests, also important for pharmacogenetic research. Furthermore, the recently opened Center for Hematology and Regenerative Medicine, with a clear translational emphasis, offers an opportunity for studying drug metabolism and toxicity in vitro by use of human hepatocytes.
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| 6. |
- Eriksson, Niclas, et al.
(författare)
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Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range : a RE-LY genomics substudy
- 2016
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 17:13, s. 1425-1439
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. Materials & methods: In total, 982 warfarin-treated patients from the RE-LY trial were studied. Results: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R-2 by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. Conclusions: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.
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| 7. |
- 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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| 8. |
- Farzan, N, et al.
(författare)
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Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium
- 2017
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 18:10, s. 931-943
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Tidskriftsartikel (refereegranskat)abstract
- Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. Materials & methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.
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| 9. |
- Gil, JP
(författare)
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Amodiaquine pharmacogenetics
- 2008
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 9:10, s. 1385-1390
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Tidskriftsartikel (refereegranskat)abstract
- Amodiaquine is a central drug in the new global strategy of combination therapies for the control of malaria. Amodiaquine is mainly metabolized hepatically towards its major active metabolite desethylamodiaquine, by the polymorphic P450 isoform CYP2C8. Amodiaquine is associated with rare but serious side effects, as well as with relatively frequent mild ones. These are expected to be at least partially related to CYP2C8 alleles. Pharmacogenetic knowledge of amodiaquine exposed populations is important for pharmacovigilance issues and in being a first step for future realistic applications from a personal medicine perspective.
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| 10. |
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| 11. |
- Gill, JP, et al.
(författare)
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CYP2C8 and antimalaria drug efficacy
- 2007
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 8:2, s. 187-198
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Tidskriftsartikel (refereegranskat)abstract
- Malaria is a major infectious disease. In the last 10 years it has killed more than 20 million people, mainly small children in Africa. The highly efficacious artemisinine combination therapy is being launched globally, constituting the main hope for fighting the disease. Amodiaquine is a main partner in these combinations. Amodiaquine is almost entirely metabolized by the polymorphic cytochrome P450 (CYP) isoform 2C8 to the pharmacologically active desethylamodiaquine. The question remains whether the efficacy of amodiaquine is affected by the gene polymorphism. Genotype-inferred low metabolizers are found in 1–4% of African populations, which corresponds to millions of expected exposures to the drug. In vivo pharmacokinetic data on amodiaquine is limited. By combining it with published in vitro pharmacodynamic and drug metabolism information, we review and predict the possible relevance, or lack of, of CYP2C8 polymorphisms in the present and future efficacy of amodiaquine. Chloroquine and dapsone, both substrates of CYP2C8, are also discussed in the same context.
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| 12. |
- Gomez, A, et al.
(författare)
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Epigenetic and microRNA-dependent control of cytochrome P450 expression: a gap between DNA and protein
- 2009
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 10:7, s. 1067-1076
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Tidskriftsartikel (refereegranskat)abstract
- Although pharmacogenetics has been instrumental in describing interindividual variations in drug metabolism, epigenetic factors offer another blanket of information that could give a more vivid picture and help in developing a more personalized therapy. The dynamic aspect of epigenetics could likewise provide more definite answers to the role of changing environmental factors in drug response: the bridge that connects the environment to the genome. In this review we discuss known epigenetic and microRNA-dependent regulation of the human drug-metabolizing cytochromes P450 to help explain the unknown factors of variable drug response.
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| 13. |
- Gomez, A, et al.
(författare)
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Expression of CYP2W1 in colon tumors: regulation by gene methylation
- 2007
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 8:10, s. 1315-1325
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: CYP2W1 is a novel enzyme shown to be selectively expressed in rat fetal colon and in human colon cancer and has previously been suggested as a potential drug target for cancer therapy. Here, the expression and gene methylation of CYP2W1 were analyzed in human colon carcinoma cell lines, colon tumors and in corresponding normal colon tissue. Methods: CYP2W1 mRNA and protein expression in HepG2 and Caco-2TC7 cells and normal colon and colon tumor tissue samples were analyzed using real-time PCR and Western blotting. CYP2W1 gene methylation status in the same samples was analyzed using the sodium bisulfite sequencing method. Results & Discussion: CYP2W1 mRNA was detected in all (n = 39) tumor samples analyzed. Moreover, in 60% (12/20) of the colon tumors, CYP2W1 mRNA levels were substantially higher than in corresponding normal tissues. CYP2W1 protein was detected in most of the colon tumor samples analyzed (n = 16), which appeared to be of two apparent phenotypes: those with five- to ten-fold induced CYP2W1 (approximately 50% of the tumors), and those with low expression, harboring similar or only slightly higher amounts of CYP2W1 as compared with surrounding control tissue. Methylation analysis of the CpG island in the exon 1–intron 1 junction of the CYP2W1 gene from both cell lines, tumors and normal tissues revealed that demethylated CpG dinucleotides appeared as a requirement for high CYP2W1 gene expression. Conclusion: The expression of CYP2W1 is colon tumor-specific and is associated with methylation status of the CYP2W1 gene, suggesting a potential causal link between the gene hypomethylation and its enhanced expression.
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| 14. |
- Green, Henrik, 1975-
(författare)
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Pharmacogenomics of importance for paclitaxel chemotherapy
- 2008
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 9:6, s. 671-674
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Tidskriftsartikel (refereegranskat)abstract
- Paclitaxel (Taxol®) has a broad activity spectrum and is clinically used, often in combination with carboplatin, to treat breast, ovarian and lung cancer. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. However, so far only genetic variants of ABCB1 have been indicated to be associated with response and pharmacokinetics of paclitaxel. Commercially, the patent on paclitaxel has expired: however, from a healthcare perspective, it would be beneficial to identify patients with risk of poor response or high risk of toxicity to reduce hospitalization costs. This artiicle focuses on the pharmacogenomic background for paclitaxel response and interindividual variability.
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| 15. |
- Gunes, Arzu, et al.
(författare)
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Influence of genetic polymorphisms, smoking, gender and age on CYP1A2 activity in a Turkish population
- 2009
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 10:5, s. 769-778
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To study the variation in CYP1A2 activity in relation to smoking, gender, age and CYP1A2 polymorphisms. MATERIALS & METHODS: CYP1A2 activity was determined by plasma paraxanthine:caffeine ratio (17X:137X) 4 h after the intake of a standardized cup of coffee in 146 Turkish healthy volunteers. Seven CYP1A2 polymorphisms (-3860G>A, -3113G>A, -2467del/T, -739T>G, -729C>T, -163C>A and 5347T>C) were analyzed. RESULTS: The 17X:137X ratios were increased in smokers (p < 0.0001) and tended to be higher in men both among nonsmokers (p = 0.051) and smokers (p = 0.064). Age-related differences were observed only among nonsmoking women (p = 0.024). The -163C>A polymorphism correlated with 17X:137X ratios only in smokers (p = 0.006). Furthermore, increased 17X:137X ratios were observed in CYP1A2 haplotype H4 (-3860G, -3113G, -2467del, -739T, -729C, -163A and 5347T) carriers in the overall study population (p = 0.026). Multiple regression analyses including smoking, gender, -163C>A genotype and age revealed a significant influence of smoking (p < 0.0001) and gender (p = 0.002) in the overall study population. However, in nonsmokers only the influence of gender remained significant (p = 0.021), while in smokers the influence of the -163C>A genotype held the statistical significance (p = 0.019). The influence of haplotype H4 remained significant (p = 0.028) in the overall study population in similar analyses. CONCLUSION: Smoking has the strongest impact on CYP1A2 activity, while gender and haplotype H4 showed marginal effects. The influence of the -163C>A polymorphism on CYP1A2 activity in smokers suggests an effect on the inducibility of the enzyme.
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| 16. |
- Gunes, Arzu, et al.
(författare)
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Variation in CYP1A2 activity and its clinical implications : influence of environmental factors and genetic polymorphisms
- 2008
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 9:5, s. 625-637
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Forskningsöversikt (refereegranskat)abstract
- CYP1A2 is involved in the metabolism of several widely used drugs and endogenous compounds, and in the activation of procarcinogens. Both genetic and environmental factors influence the activity of this enzyme. The current knowledge regarding factors influencing the activity of CYP1A2 is summarized in this review. Substrates, inhibitors and inducers of CYP1A2 activity, as well as phenotyping probes, are discussed. The functional significance and clinical importance of CYP1A2 gene polymorphisms are reviewed and interethnic differences in the distribution of CYP1A2 variant alleles and haplotypes are summarized. Finally, future perspectives for the possible clinical applications of CYP1A2 genotyping are discussed.
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| 17. |
- Hallberg, Pär, et al.
(författare)
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Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough : a genome-wide association study in a Swedish population
- 2017
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Ingår i: Pharmacogenomics (London). - : FUTURE MEDICINE LTD. - 1462-2416 .- 1744-8042. ; 18:3, s. 201-213
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Tidskriftsartikel (refereegranskat)abstract
- Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.
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| 18. |
- Hamberg, Anna-Karin, et al.
(författare)
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Pharmacogenetics-based warfarin dosing in children
- 2014
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 15:3, s. 361-374
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Forskningsöversikt (refereegranskat)abstract
- Clinical factors, demographic variables and variations in two genes, CYP2C9 and VKORC1, have been shown to contribute to the variability in warfarin dose requirements among adult patients. Less is known about their relative importance for dose variability in children. A few small studies have been reported, but the results have been conflicting, especially regarding the impact of genotypes. In this article, we critically review published pharmacogenetic-based prediction models for warfarin dosing in children, and present results from a head-to-head comparison of predictive performance in a distinct cohort of warfarin-treated children. Finally we discuss what properties a prediction model should have, and what knowledge gaps need to be filled, to improve warfarin therapy in children of all ages.
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| 19. |
- Hassan, M, et al.
(författare)
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Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation
- 2013
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 14:1, s. 75-87
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cell transplantation (HSCT) is a curative treatment for several malignant and nonmalignant disorders. Busulfan (Bu) and cyclophosphamide (Cy) are the most commonly used alkylators in high-dose pretransplant conditioning for HSCT; a treatment that is correlated with drug-related toxicity and relapse. Pharmacogenetic investigations have shown that CYP450, as well as aldehyde dehydrogenase, are clearly involved with Cy metabolism and are associated with altered treatment response, Cy metabolism and the unique stem-cell sparing capacity. Moreover, glutathione-S-transferase isoenzymes have been associated with cellular outward transport of various alkylating agents, including Cy metabolites, melphalan, Bu and chlorambucil. A shift from genetic-based studies to whole-genome-based investigations of Cy- and Bu-associated markers may contribute to personalizing the conditioning therapy and enhancing the clinical outcome of HSCT.
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| 20. |
- Ingelman-Sundberg, M, et al.
(författare)
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Human liver spheroids in chemically defined conditions for studies of gene-drug, drug-drug and disease-drug interactions
- 2018
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 19:14, s. 1133-1138
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Tidskriftsartikel (refereegranskat)abstract
- Recent phenotypically and functionally relevant human hepatic in vitro systems combine the ability to preserve interindividual molecular differences between patients’ livers in culture with the accessibility and high-throughput compatibility of in vitro assays. These features facilitate studies of specific genetic polymorphisms by using cells from donors with defined variants of interest or by selective gene knock-down experiments. Furthermore, these models constitute promising tools to evaluate drug–drug interactions as well as the effects of liver diseases on drug pharmacokinetics in co-cultures of hepatocytes and non-parenchymal cells. In the near future, we anticipate that these tools will be of high relevance for predicting the in vivo kinetics, toxicity and drug–drug interactions of drug candidates already during preclinical development.
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| 21. |
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| 22. |
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| 23. |
- Ingelman-Sundberg, M, et al.
(författare)
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The past, present and future of pharmacoepigenomics
- 2010
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 11:5, s. 625-627
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Tidskriftsartikel (refereegranskat)abstract
- A significant number of instances of interindividual variability in drug response, where a clear phenotypic consequence is evident in the population, have not yet been associated with variations in gene sequence. Epigenetics, along with, for example, drug interactions and disease, provides answers to some of these inconsistencies. The role of epigenetics in drug response has just started to be perceived, but its impending influence on drug metabolism and disposition promises to be important. Research in this area can provide us with novel mechanisms for this variation and also with novel biomarkers that can be useful for understanding drug response, as well as for the development of new drugs and which can, in addition, constitute predictive biomarkers for today’s and tomorrow’s pharmacotherapy, yielding a substantial improvement in human health.
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| 24. |
- Jukic, MM, et al.
(författare)
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Functional characterization of CYP2D7 gene variants
- 2018
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 19:12, s. 931-936
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Tidskriftsartikel (refereegranskat)abstract
- The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.
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| 25. |
- Karlsson Sundbaum, Johanna, et al.
(författare)
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Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate
- 2021
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 22:15, s. 973-982
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.
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| 26. |
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| 27. |
- Lauschke, VM, et al.
(författare)
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CYP3A5 is unlikely to mediate anticancer drug resistance in hepatocellular carcinoma
- 2019
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 20:15, s. 1085-1092
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Tidskriftsartikel (refereegranskat)abstract
- Recently, it was published that CYP3A5 contributes to chemotherapeutic drug resistance in a wide range of solid tumors, including hepatocellular carcinoma. However, CYP3A5 is highly polymorphic and 90% of Caucasians are homozygous for the loss-of-function allele CYP3A5*3. Here, we evaluate the relationship between CYP3A5 genotype and expression level of both CYP3A5 transcripts and protein in biopsies from 19 pairs of liver tumors and corresponding peritumoral tissue. We find that CYP3A5 transcript levels are reduced compared with peritumoral controls. Moreover, we do not detect CYP3A5 protein in homozygous CYP3A5*3 carriers and no relative increase of CYP3A5 in tumoral tissue of CYP3A5*1 carriers. We conclude that anticancer drug resistance is unlikely to be caused by increased CYP3A5 expression.
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| 28. |
- Lauschke, VM, et al.
(författare)
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Requirements for comprehensive pharmacogenetic genotyping platforms
- 2016
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 17:8, s. 917-924
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Tidskriftsartikel (refereegranskat)abstract
- Recent research highlighted the large extent of rare variants in pharmacogenes and, on this basis, it was estimated that rare variants account for 30–40% of the functional variability in pharmacogenes. It has been proposed that comprehensive next-generation sequencing (NGS)-based sequencing of pharmacogenes could soon be a cost-effective methodology for clinical routine genotyping. Yet, multiple challenges on technical, interpretative and ethical levels need to be overcome to enable the reasonable dissemination of comprehensive pharmacogenetic genotyping, that includes rare genetic variation, into clinical practice. We argue that current pre-emptive pharmacogenetic testing cannot be based on comprehensive approaches but needs to be restricted to validated variants. Rather, comprehensive strategies should only be used for retrospective analyses of patients exhibiting unanticipated drug responses. Thereby, subsequent to computational analyses and functional validations, emerging variants with confirmed functional relevance can be incorporated into candidate genotyping strategies, thus refining and enhancing future pre-emptive genetic testing.
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| 29. |
- Lee, Mi-Young, et al.
(författare)
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Role of cytochrome P450 2C8*3 (CYP2C8*3) in paclitaxel metabolism and paclitaxel-induced neurotoxicity
- 2015
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Ingår i: Pharmacogenomics (London). - : Future Medicine. - 1462-2416 .- 1744-8042. ; 16:9, s. 929-937
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The CYP2C8*3 allele has been suggested as a risk factor for paclitaxel-induced neuropathy but the data hitherto published are conflicting. Materials and methods: In total 435 patients were investigated with respect to maximum neuropathy grade and accumulated paclitaxel dose. The enzymatic properties of CYP2C8.3 variant were analyzed using heterologous mammalian HEK293 cell expression system. Results: No significant association between CYP2C8*3 allele and neuropathy was found, although a trend was observed. The paclitaxel and amodiaquine metabolism by CYP2C8.3 were found similar to CYP2C8.1, whereas CYP2C8.3 was more efficient in the metabolism of rosiglitazone. Conclusion: These results indicate a difference in substrate specificity between CYP2C8.1 and CYP2C8.3; however, the CYP2C8*3 allele has no major impact on paclitaxel metabolism in vitro or of paclitaxel-induced neuropathy in vivo. Original submitted on 6 February 2015; revision submitted on 9 April 2015
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| 30. |
- Leusink, M., et al.
(författare)
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A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering
- 2016
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 17:6, s. 583-591
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome. Patients & methods: In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10-4 (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE. Results: No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 × 10-4). Conclusion: The GRS was associated with statin response, but the small effect size (∼2% of the average low-density lipoprotein cholesterol reduction) limits applicability. © Future Medicine Ltd 2016.
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| 31. |
- Mao, Mao, et al.
(författare)
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Flavin-containing monooxygenase 3 polymorphisms in 13 ethnic populations from Europe, East Asia and sub-Saharan Africa : frequency and linkage analysis
- 2009
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 10:9, s. 1447-1455
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To investigate intra- and inter-ethnic differences in three widespread (E158K, V257M and E308G) and two African-specific (D132H and L360P) flavin-containing monooxygenase 3 (FMO3) polymorphisms. MATERIALS & METHODS: Allele frequencies were determined by TaqMan allelic discrimination assay in 2152 healthy volunteers from Europe (Swedes, Italians and Turks), East Asia (Japanese) and sub-Saharan Africa (nine ethnic groups covering eastern, southern and western regions), followed by haplotype and linkage analysis. RESULTS: Significant subpopulation differences (p < 0.001) in allele frequencies were found for E158K, V257M and E308G in Europeans and regional differences (p < 0.01) for D132H among Africans. No carrier of P360 was identified. Cis-linkage between G308 and K158 was confirmed with the compound variant (K158/G308) being found in a high proportion (12.0-38.3%) of non-African subjects, but rarely (1.3%) among Africans. CONCLUSIONS: Distribution of functionally relevant FMO3 polymorphisms varies not only between ethnicities but also within. The K158/G308 variant may have potential clinical importance primarily in non-African populations due to its low prevalence in Africa.
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| 32. |
- Margolin, S, et al.
(författare)
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CYP2D6 and adjuvant tamoxifen: possible differences of outcome in pre- and post-menopausal patients
- 2013
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 14:6, s. 613-622
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Previous studies on CYP2D6 activity and the effect of adjuvant tamoxifen in breast cancer are inconsistent. We analyzed the impact of the CYP2D6 polymorphism in pre- and post-menopausal patients that were adherent to tamoxifen treatment for at least a year. Materials & methods: A total of 382 breast cancer patients prescribed adjuvant tamoxifen for 5 years constituted the study-base. Clinical information, including compliance and outcome, was retrieved from medical records. Comprehensive CYP2D6 genotyping was performed and translated into predicted metabolic activity. Results & conclusion: In patients adherent to tamoxifen for at least one year (n = 313) there was an association between reduced CYP2D6 activity (≤50% of normal) and recurrence (p = 0.025) and breast cancer-specific mortality (p = 0.034). In a multivariable analysis, CYP2D6 remained an independent predictor of outcome. In a subgroup analysis, the effect of CYP2D6 seemed to derive mainly from premenopausal patients, which represents a new finding that needs validation in a larger study sample. Original submitted 13 November 2012; Revision submitted 1 March 2013
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| 33. |
- Matic, Maja, et al.
(författare)
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Effect of UGT2B7-900G > A (-842G > A; rs7438135) on morphine glucuronidation in preterm newborns: results from a pilot cohort
- 2014
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Ingår i: Pharmacogenomics. - 1462-2416 .- 1744-8042. ; 15:12, s. 1589-1597
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Assess association between UGT2B7 polymorphism -900G>A (rs7438135, also known as -842G>A) with morphine kinetics in preterm newborns undergoing mechanical ventilation. Materials & methods: Thirty-four infants were enrolled in a randomized clinical trial and allocated to rapid sequence intubation with remifentanil (1 mu g/kg) or morphine (0.3 mg/kg). The latter group was included in our study. Results: Morphine plasma concentrations at 20 min post intubation were associated with postnatal age (p = 0.017) and UGT2B7 -900G>A (p = 0.036). UGT2B7 -900A allele carriers (n = 13) had lower morphine levels compared with UGT2B7 -900G/G patients (n = 2). Morphine-3-glucuronide and morphine-6-glucuronide plasma concentrations were only found to be associated with gestational and postnatal age. However, -900A allele carriers had a higher morphine-3-glucuronide: morphine metabolic ratio compared with patients genotyped as -900G/G (p = 0.005), as determined by linear regression. Conclusion: Our small pilot study illustrates that in addition to gestational and postnatal age, the UGT2B7 -900G>A polymorphism significantly alters morphine pharmacokinetics in preterm infants.
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| 34. |
- Mukonzo, JK, et al.
(författare)
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CYP2B6 genotype-based efavirenz dose recommendations during rifampicin-based antituberculosis cotreatment for a sub-Saharan Africa population
- 2016
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 17:6, s. 603-613
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To assess genotype effect on efavirenz (EFV) pharmacokinetics, treatment outcomes and provide genotype-based EFV doses recommendations during for tuberculosis (TB)-HIV-1 cotreatment. Materials & methods: EFV concentrations from 158 HIV-TB co-infected patients treated with EFV/lamivudine/zidovidine and rifampicin were analyzed. Genotype and CD4 and viral load data were analyzed using a population PK model. Results: Simulated AUCs for 600 mg EFV dose were 1.2- and 2.4-times greater than the product label for Ugandans in general and CYP2B6*6/*6 genotypes respectively. EFV daily doses of 450 and 250 mg for Ugandans and CYP2B6*6/*6 genotypes, respectively, yielded simulated exposures comparable to the product label. Conclusions: Around 450 and 250 mg daily doses might meet EFV dosing needs of HIV-TB infected Ugandans in general and CYP2B6*6/*6 genotypes, respectively.
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| 35. |
- Nyberg, F, et al.
(författare)
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Interstitial lung disease in gefitinib-treated Japanese patients with non-small-cell lung cancer: genome-wide analysis of genetic data
- 2011
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 12:7, s. 965-975
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate potential relationships between SNPs and acute interstitial lung disease (ILD) events in Japanese non-small-cell lung cancer patients receiving gefitinib. Materials & methods: Japanese non-small-cell lung cancer patients treated with gefitinib from a prospective pharmacoepidemiological cohort with a nested case–control study component (‘CCS’; 52 ILD cases, 139 controls) and a retrospective study (28 ILD cases, 55 controls) were genotyped for nearly 500,000 SNPs. Associations between genotype and ILD were evaluated using Fisher’s exact test and logistic regression modeling, and false discovery rate analysis was used to adjust for the large number of statistical tests. Results: The CCS data provided some false discovery rate evidence that the significance of top-ranking SNPs exceeded levels expected by chance, suggesting some genuine associations. However, replication analyses using retrospective study data were not supportive and there was little evidence of strong genetic associations from a combined analysis. Adjustment of CCS analyses for clinical variables provided little additional convincing evidence. Significant gene–gene interactions between SNP pairs using CCS data were not confirmed in retrospective study replication analyses. Conclusion: Although it is not possible to exclude genetic influences in ILD etiology, common sequence variation is unlikely to explain a major component of ILD risk. Our top results may provide a useful hypothesis-generating starting point for further research. Presented, in part, at the 26th ICPE: International Conference on Pharmacoepidemiology & Therapeutic Risk Management, Brighton, UK, 19–22 August 2010. Original submitted 1 December 2010; Revision submitted 22 February 2011
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| 36. |
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| 37. |
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| 38. |
- Parra, Esteban J., et al.
(författare)
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Genome-wide association study of warfarin maintenance dose in a Brazilian sample
- 2015
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 16:11, s. 1253-1263
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. Methods: Patients receiving low (<= 20 mg/week; n = 180) or high stable warfarin doses (>= 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom (R) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. Results: Genome-wide signals (p <= 5 x 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 x 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 x 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. Conclusion: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose.
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| 39. |
- Pisanu, Claudia, et al.
(författare)
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Recent trends on the role of epigenomics, metabolomics and noncoding RNAs in rationalizing mood stabilizing treatment
- 2018
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 19:2, s. 129-143
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Forskningsöversikt (refereegranskat)abstract
- Mood stabilizers are the cornerstone in treatment of mood disorders, but their use is characterized by high interindividual variability. This feature has stimulated intensive research to identify predictive biomarkers of response and disentangle the molecular bases of their clinical efficacy. Nevertheless, findings from studies conducted so far have only explained a small proportion of the observed variability, suggesting that factors other than DNA variants could be involved. A growing body of research has been focusing on the role of epigenetics and metabolomics in response to mood stabilizers, especially lithium salts. Studies from these approaches have provided new insights into the molecular networks and processes involved in the mechanism of action of mood stabilizers, promoting a systems-level multiomics synergy. In this article, we reviewed the literature investigating the involvement of epigenetic mechanisms, noncoding RNAs and metabolomic modifications in bipolar disorder and the mechanism of action and clinical efficacy of mood stabilizers.
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| 40. |
- Rembeck, Karolina, et al.
(författare)
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Impact of IL28B, ITPA and PNPLA3 genetic variants on therapeutic outcome and progression of hepatitis C virus infection
- 2015
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 16:10, s. 1179-1188
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Tidskriftsartikel (refereegranskat)abstract
- Chronic HCV infection comprises a broad spectrum of liver disease, ranging from no or minimal activity to active hepatitis that in time may progress to severe liver fibrosis, cirrhosis and hepatocellular carcinoma if left untreated. This review describes the impact of genetic variants of interleukin 28B (IL28B; also known as interferon-lambda 3), inosine triphosphate pyrophosphatase (ITPA) and patatin-like phospholipase domain-containing 3 (PNPLA3) on therapeutic outcome and liver disease severity in HCV-infected patients.
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| 41. |
- Ringnér, Markus, et al.
(författare)
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Analyzing array data using supervised methods
- 2002
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 3:3, s. 403-415
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Forskningsöversikt (refereegranskat)abstract
- Pharmacogenomics is the application of genomic technologies to drug discovery and development, as well as for the elucidation of the mechanisms of drug action on cells and organisms. DNA microarrays measure genome-wide gene expression patterns and are an important tool for pharmacogenomic applications, such as the identification of molecular targets for drugs, toxicological studies and molecular diagnostics. Genome-wide investigations generate vast amounts of data and there is a need for computational methods to manage and analyze this information. Recently, several supervised methods, in which other information is utilized together with gene expression data, have been used to characterize genes and samples. The choice of analysis methods will influence the results and their interpretation, therefore it is important to be familiar with each method, its scope and limitations. Here, methods with special reference to applications for pharmacogenomics are reviewed.
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| 42. |
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| 43. |
- Shalimova, Alena, et al.
(författare)
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Therapy response prediction in major depressive disorder : current and novel genomic markers influencing pharmacokinetics and pharmacodynamics
- 2021
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Ingår i: Pharmacogenomics (London). - : Future Medicine. - 1462-2416 .- 1744-8042. ; 22:8, s. 485-503
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Forskningsöversikt (refereegranskat)abstract
- Major depressive disorder is connected with high rates of functional disability and mortality. About a third of the patients are at risk of therapy failure. Several pharmacogenetic markers especially located in CYP450 genes such as CYP2D6 or CYP2C19 are of relevance for therapy outcome prediction in major depressive disorder but a further optimization of predictive tools is warranted. The article summarizes the current knowledge on pharmacogenetic variants, therapy effects and side effects of important antidepressive therapeutics, and sheds light on new methodological approaches for therapy response estimation based on genetic markers with relevance for pharmacokinetics, pharmacodynamics and disease pathology identified in genome-wide association study analyses, highlighting polygenic risk score analysis as a tool for further optimization of individualized therapy outcome prediction.
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| 44. |
- Siest, G, et al.
(författare)
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Systems medicine, personalized health and therapy
- 2015
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 16:14, s. 1527-39
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The 7th Santorini Conference was held in Santorini, Greece, and brought together 200 participants from 40 countries in several continents, including Europe, USA but also Japan, Korea, Brazil and South Africa. The attendees had the opportunity to: listen to 60 oral presentations; participate in two lunch symposia; look at 103 posters, which were divided in two groups (‘systems medicine and environment’ and ‘pharmacogenomics and cancer’) and attend a dedicated exhibition with six companies. The meeting was organized by the Institut National de la Santé et de la Recherche Médicale (INSERM) U1122; IGE-PCV and by ‘Biologie Prospective’ with the collaboration of the European Society of Pharmacogenomics and Theranostics (ESPT), under the auspices of international organizations (e.g., International Federation of Clinical Chemistry and Laboratory medicine [IFCC], European Federation of Clinical Chemistry and Laboratory Medicine [EFLM], European Diagnostic Manufacturers Association [EDMA], Federation of European Pharmacological Societies [EPHAR], European Science Foundation [ESF]). The 3 days of the conference stimulated intensive discussions on systems biology and the influence of omics technologies on personalized health. Sixty speakers were invited or selected from early abstracts and gave presentations on the following topics: From systems biology to systems medicine/pharmacology; Omics/translating pharmacogenomics/proteomic biomarkers/metabolomics; Human nutrition and health/personalized medicine. We are summarizing here the main topics and presentations, according to the successive sessions.
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| 45. |
- Sim, S, et al.
(författare)
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Effect of CYP2C19 and CYP2D6 genotype on tamoxifen treatment outcome indicates endogenous and exogenous interplay
- 2018
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 19:13, s. 1027-1037
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Tidskriftsartikel (refereegranskat)abstract
- Aim: We investigated the interaction of CYP2C19 and CYP2D6 genotype on clinical outcome in tamoxifen-treated breast cancer patients. Materials & methods: A cohort of 306 patients on tamoxifen treatment for a minimum of 1 year were employed to analyze the effect of genotype-predicted phenotype on relapse-free survival. Results & conclusion: We show that the group with worst outcome and highest risk of relapse is that of 2C19↑–2D6↓ (hazard ratio: 2.94), when adjusting for age, Nottingham prognostic index and adjuvant chemotherapy. Furthermore, the effect of 2C19↑–2D6↓genotype-predicted phenotype is greatly enhanced in premenopausal patients (hazard ratio: 21.08). We hypothesize that poor bioactivation of tamoxifen in patients with low CYP2D6 activity and high CYP2C19 metabolism represents a tamoxifen-treated patient group that has the worst clinical outcome.
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| 46. |
- Sim, S, et al.
(författare)
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Pharmacogenetic impact of docetaxel on neoadjuvant treatment of breast cancer patients
- 2018
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 19:16, s. 1259-1268
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This study aimed to investigate the effect of CYP3A4 and CYP3A5 genotypes on clinical outcomes of docetaxel treatment. Patients & methods: In the PROMIX trial, 150 breast cancer patients received docetaxel preoperatively. CYP3A4 and CYP3A5 genotype combinations were transformed into total CYP 3A phenotypes. Results: Seven patients were characterized as poor metabolizer (PM), 22 patients as extensive metabolizer and 121 patients as intermediate metabolizer. The frequency of grade 3/grade 4 adverse events was higher in the PM group (p = 0.002). One PM subject who basically lacked enzyme activity died from typhlitis. Total 45 recurrences were reported after a median of 5-year follow-up; none of these was PM. Conclusion: The allelic variants CYP3A4*22 and CYP3A5*3 contribute to the interpatient variations of docetaxel.
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| 47. |
- Sipeky, C, et al.
(författare)
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4th ESPT Conference: pharmacogenomics and personalized medicine - research progress and clinical implementation
- 2019
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 20:15, s. 1063-1069
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Tidskriftsartikel (refereegranskat)abstract
- The Fourth European Society of Pharmacogenomics and Personalized Therapy biennial conference was organized in collaboration with the Italian Society of Personalized Medicine (SIMeP) and was held at Benedictine Monastery of San Nicolò l’Arena in Catania, Sicily (Italy) on 4–7 October 2017. The congress addressed the research progress and clinical implementation in pharmacogenomics and personalized medicine. The Fourth European Society of Pharmacogenomics and Personalized Therapy congress brought together leading international scientists and healthcare professionals actively working in the fields of pharmacogenomics and personalized therapy. Altogether, 25 speakers in 15 session comprehensively covered broad spectrum of pharmacogenetics and pharmacogenomics research, clinical applications in different clinical disciplines attended by 270 delegates.
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| 48. |
- Soderberg, MM, et al.
(författare)
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Pharmacogenetics of olanzapine metabolism
- 2013
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 14:11, s. 1319-1336
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics of the atypical antipsychotic, olanzapine, display large interindividual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need for individualized dosing in order to avoid concentration-dependent adverse effects or therapeutic failure. Genetically determined differences in olanzapine metabolism represent a less studied source of variability in comparison to environmental and physiological factors. In this review, we summarize available in vitro and in vivo data addressing the influence of polymorphisms in drug-metabolizing enzymes on olanzapine serum exposure. The polymorphic CYP2D6 enzyme appears to have no significant influence on olanzapine steady-state serum concentrations. The formation of the various olanzapine metabolites is influenced by polymorphisms in the genes coding for CYP1A2, CYP1A expression regulator AHR, UGT1A4 and UGT2B10, as well as FMO3. An impact on steady-state olanzapine serum concentrations has been suggested for variants of CYP1A2 and UGT1A4, with somewhat conflicting findings. The potential involvement of FMO1 and CYP3A43 in olanzapine disposition has also been suggested but needs future validation.
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| 49. |
- Stenstedt, K, et al.
(författare)
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CYP2W1 polymorphism: functional aspects and relation to risk for colorectal cancer
- 2013
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Ingår i: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 14:13, s. 1615-1622
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This study aims to investigate the possible association between the risk of colorectal cancer (CRC) and allelic variants of CYP2W1 and their functional properties. Materials & methods: The distribution of three different CYP2W1 alleles (CYP2W1*1, CYP2W1*2 and CYP2W1*6) in 1785 CRC patients and 1761 healthy blood donors was determined using the TaqMan® (Applied Biosystems, CA, USA) allelic discrimination assay or allele-specific amplification. Corresponding gene products (CYP2W1.1, CYP2W1.2 and CYP2W1.6) were expressed in human colon cancer SW480 cells and their activities towards two different substrates, the duocarmycin analogs ICT2706 and ICT2726, were monitored. Results: No significant differences in the distribution of CYP2W1*1, CYP2W1*2 and CYP2W1*6 alleles were found between CRC patients and controls. The CYP2W1.1, CYP2W1.2 and CYP2W1.6 variant enzymes were expressed at the similar levels in the transfected SW480 cells and had comparable kinetics in terms of the metabolism of the duocarmycin ICT2726, as well as in the bioactivation of ICT2706 into a cytotoxic product. Conclusion: These epidemiological data obtained from a large population of CRC patients and controls cannot confirm the previously suggested decreased risk for CRC among carriers of CYP2W1*2. On the molecular level, this conclusion is further supported by the similar catalytic characteristics of the CYP2W1.1, CYP2W1.2 and CYP2W1.6 variants of CYP2W1. Original submitted 19 March 2013; Revision submitted 15 July 2013
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| 50. |
- Sundbaum, Johanna, et al.
(författare)
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MTHFR, TYMS and SLCO1B1 polymorphisms and adverse liver effects of methotrexate in rheumatoid arthritis
- 2020
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Ingår i: Pharmacogenomics (London). - London : Future Medicine. - 1462-2416 .- 1744-8042. ; 21:5, s. 337-346
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate whether variants of MTHFR, TYMS and SLCO1B1 are associated with alanine aminotransferase (ALT) elevation in rheumatoid arthritis patients starting methotrexate (MTX).Patients & Methods: Clinical and laboratory data were collected from the start of MTX treatment. Genotyping of MTHFR, TYMS and SLCO1B1 was performed. Univariate and multiple logistic regression were used for statistical analysis.Results: 34 out of 369 patients experienced ALT >1.5xULN less than 6 months from start. MTHFR A1298C (rs1801131) was nominally associated with an ALT > 1.5 xULN within 6 months after the start of MTX (OR = 1.7 [95% CI: 1.04–2.9]; p = 0.03), but did not pass correction for multiple testing. A multiple model containing MTHFR 1298C and clinical factors predicted the outcome (C-statistic 0.735). TYMS and SLCO1B1 were not associated with the outcome.Conclusions: A model containing MTHFR 1298C and clinical factors might predict risk of early ALT elevation.
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