| 1. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 2. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 3. |
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| 4. |
- Oosten, Astrid W, et al.
(författare)
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A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients.
- 2017
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 56:7, s. 733-746
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.METHODS: Blood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.RESULTS: A one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration-time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m(2) increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m(2). The clearance of morphine or its metabolites was not found to be correlated with treatment failure.CONCLUSION: The influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome. Dutch Trial Register ID: NTR4369.
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| 5. |
- van der Bol, Jessica M., et al.
(författare)
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Cigarette smoking and irinotecan treatment : Pharmacokinetic interaction and effects on neutropenia
- 2007
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 25:19, s. 2719-2726
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes and potentially affect treatment outcome with substrate drugs. The purpose of this study was to determine the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan. Patients and Methods A total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/m(2) or 600 mg flat-fixed dose irinotecan. Results In smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng . h/mL/mg; P = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng . h/mL/mg; P < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5; P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.10; 95% CI, 0.02 to 0.43; P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149). Conclusion This study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.
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| 6. |
- Elens, Laure, et al.
(författare)
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Genetic Predisposition to Poor Opioid Response in Preterm Infants : Impact of KCNJ6 and COMT Polymorphisms on Pain Relief after Endotracheal Intubation
- 2016
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:4, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- Background: Single-nucleotide polymorphisms in genes involved in pain control might predispose to exaggerated sensitivity or difference in opioid analgesic effect. The relevance of the KCNJ6 -1250G>A (rs6517442, c.-1787G>A) and the catecholamine-O-methyltransferase (COMT) c.472G>A (rs4680, Val 158 Met) single-nucleotide polymorphisms were studied in preterm infants needing intubation and randomized to a premedication strategy including remifentanil (n 17) or morphine (n 17). Methods: Pain was scored with Astrid Lindgren and Lund Children's Hospital Pain Assessment Scale every 30 minutes for 6 hours. The pain relief provided by the opioids was compared between the different KCNJ6 and COMT genotypes. Results: Infants homozygous for the KCNJ6 -1250A allele had an increased duration after intubation to achieve a score indicating no pain compared with infants with the A/G or G/G genotypes (182 ± 30, 109 ± 29, and 60 ± 21 minutes, respectively; Logrank 7.5, P 0.006). Similarly, the duration was increased in individuals with the COMT Val/Val alleles compared with Val/Met and Met/Met (285 ± 37, 137 ± 25, and 63 ± 15 minutes, respectively; Logrank 14.4, P 0.0021). Cox proportional hazards analysis confirmed that the variation in both genes was independently associated with susceptibility to respond to therapy. Conclusion: We conclude that the KCNJ6 -1250A and COMT 158 Val alleles are predisposing preterm newborns to diminished opioid-induced pain relief.
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| 7. |
- Malentacchi, Francesca, et al.
(författare)
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Is laboratory medicine ready for the era of personalized medicine? A survey addressed to laboratory directors of hospitals/academic schools of medicine in Europe
- 2015
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Ingår i: Clinical Chemistry and Laboratory Medicine. - : De Gruyter. - 1434-6621 .- 1437-4331. ; 53:7, s. 981-988
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Tidskriftsartikel (refereegranskat)abstract
- Developments in "-omics" are creating a paradigm shift in laboratory medicine leading to personalized medicine. This allows the increase in diagnostics and therapeutics focused on individuals rather than populations. In order to investigate whether laboratory medicine is ready to play a key role in the integration of personalized medicine in routine health care and set the state-of-the-art -knowledge about personalized medicine and laboratory medicine in Europe, a questionnaire was constructed under the auspices of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the European Society of Pharmacogenomics and Personalised Therapy (ESPT). The answers of the participating laboratory medicine professionals indicate that they are aware that personalized medicine can represent a new and promising health model, and that laboratory medicine should play a key role in supporting the implementation of personalized medicine in the clinical setting. Participants think that the current organization of laboratory medicine needs additional/relevant implementations such as (i) new technological facilities in -omics; (ii) additional training for the current personnel focused on the new methodologies; (iii) incorporation in the laboratory of new competencies in data interpretation and counseling; and (iv) cooperation and collaboration among professionals of different disciplines to integrate information according to a personalized medicine approach.
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| 8. |
- Haage, Pernilla, 1982-, et al.
(författare)
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Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
- 2018
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Ingår i: Pharmacology Research & Perspectives. - : John Wiley & Sons. - 2052-1707. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.
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| 9. |
- 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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