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Sökning: WFRF:(Wadelius Mia) > Kohnke Hugo

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1.
  • Hallberg, Pär, 1974-, et al. (författare)
  • Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
  • 2019
  • Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 40, s. 595-604
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.
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2.
  • Karlsson Sundbaum, Johanna, et al. (författare)
  • Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate
  • 2021
  • Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 22:15, s. 973-982
  • 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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3.
  • Rasmussen, Eva Rye, et al. (författare)
  • Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
  • 2020
  • Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 20:6, s. 770-783
  • Tidskriftsartikel (refereegranskat)abstract
    • Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.
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4.
  • Aomori, Tohru, et al. (författare)
  • Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 2
  • 2009
  • Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 55:4, s. 804-812
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.
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5.
  • Cavalli, Marco, et al. (författare)
  • Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate
  • 2022
  • Ingår i: Pharmacogenomics (London). - : Future Medicine. - 1462-2416 .- 1744-8042. ; 23:15, s. 813-820
  • 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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6.
  • Glimelius, Bengt, et al. (författare)
  • Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer
  • 2011
  • Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 11:1, s. 61-71
  • Tidskriftsartikel (refereegranskat)abstract
    • Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).
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7.
  • Howard, Rebecca, et al. (författare)
  • Genotyping for CYP2C9 and VKORC1 alleles by a novel point of care assay with HyBeacon® probes
  • 2011
  • Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 412:23-24, s. 2063-2069
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Coumarin anticoagulants such as warfarin are used to treat and prevent thromboembolic events in patients. The required dosage is difficult to predict and the risk of over or under anticoagulation are dependent on several environmental and clinical factors, such as concurrent medication, diet, age and genotype for polymorphisms in two genes CYP2C9 and VKORC1.METHODS: A novel fluorescent PCR genotyping assay using HyBeacon® probes, was developed to enable clinical staff to genotype the CYP2C9*2 and CYP2C9*3 alleles and the VKORC1 G-1639A polymorphism directly from unextracted blood samples. A prototype PCR instrument, Genie 1, suitable for point of care use was developed to carry out the assays. The panel of tests was validated by analysing blood samples from 156 individuals and comparing genotypes with data obtained using DNA samples from the same individuals. The accuracy of genotypes obtained with the Genie 1 was compared against results from well validated real time PCR and PCR-restriction fragment length polymorphism analysis.RESULTS: Identical results were obtained for the newly developed HyBeacon® method and the validation method in all cases except for one where no result was obtained for the VKORC1 polymorphism on the Genie instrument. The samples used for validation represented all six possible *2 and *3 allele-related CYP2C9 genotypes and all three VKORC1 G-1639A genotypes.CONCLUSIONS: We observed excellent accuracy for the newly developed method which can determine genotype in less than 2 h.
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9.
  • Kohnke, Hugo, et al. (författare)
  • Warfarin dose related to apolipoprotein E (APOE) genotype
  • 2005
  • Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 61:5-6, s. 381-8
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Warfarin is an anticoagulant which acts through interference with the recycling of vitamin K in the liver, leading to reduced activation of several clotting factors. Apolipoprotein E plays a central role in the uptake of the lipid-soluble vitamin K. The apolipoprotein E (APOE) alleles E2, E3 and E4 encode the three major isoforms of apolipoprotein E. The aim of this project was to evaluate whether variation in the APOE gene influences warfarin dose.METHODS: We genotyped APOE in 183 warfarin-treated patients. Information about warfarin dose, prothrombin time, age, gender, body weight, treatment indication and duration, other diseases and concurrent medication was taken from the patients' medical records. Cytochrome P(450) 2C9 genotyping had been performed previously, and patients were stratified according to CYP2C9 genotype.RESULTS: Patients homozygous for APOE*E4 tended to receive higher warfarin doses than others. Among CYP2C9 extensive metabolisers, APOE*E4 homozygous patients received significantly higher warfarin doses than patients with one or no E4 alleles; 56.9 compared with 34.3 and 34.6 mg/week, (Bonferroni corrected P=0.008 and 0.007, respectively). APOE genotype explains 6% of warfarin dose variance among CYP2C9 extensive metabolisers (analysis of variance, P=0.009).CONCLUSION: Previous studies have shown that individuals carrying the APOE*E4 allele have a faster uptake of lipoproteins into the liver and lower levels of circulating vitamin K than others. It is therefore plausible that patients carrying E4 alleles have an enhanced uptake of vitamin K into the liver and require higher doses of warfarin to compensate for this.
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10.
  • Pirmohamed, Munir, et al. (författare)
  • A Randomized Trial of Genotype-Guided Dosing of Warfarin
  • 2013
  • Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 369:24, s. 2294-2303
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.Methods: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639GA) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.Results: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR 4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).Conclusions: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. 
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