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- Eriksson, Niclas, 1978-
(författare)
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On the Prediction of Warfarin Dose
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.
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- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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- Alfredsson, Joakim, et al.
(författare)
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Similar outcome with an invasive strategy in men and women with Non ST-Elevation Acute Coronary Syndromes
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Gender differences in benefit from an early invasive strategy in patients with Non ST-elevation Acute Coronary Syndromes (NSTE ACS) have been debated and results are conflicting. Some studies have even indicated harm for women associated with a routine invasive strategy. Method: We included 46 455 patients ( 14 819 women (32%) and 31 636 men (68%)) from The Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), with a diagnosis of either unstable angina pectoris or non-ST-elevation myocardial infarction. All patients were admitted to intensive coronary care units in Sweden, between 2000 and 2006, and followed for 1 year. Adjustment for baseline differences between the genders was made. Results: In the non-invasive strategy arm relative risk (RR) of death was (women vs. men) 1.02 (95% CI, 0.94-1.11) and in the invasive strategy arm 1.12 (95% CI, 0.96-1.29). After adjustment for baseline differences between the genders with propensity score and discharge medication there was a trend towards lower mortality among women, RR 0.90 (95% CI, 0.82-0.99) in the early non-invasive group but still no difference in the early invasive cohort RR 0.90 (95% CI, 0.76-1.06). Results were similar with the combined end-point death/MI. The risk reduction with an invasive strategy was similar in women (RR 0.46 (95% CI 0.38-0.55)) and men (RR 0.45 (95% CI 0.40-0.52). Conclusion: In this large cohort of patients with NSTE ACS, reflecting real life management, women and men had similar outcome and similar benefit with an early invasive strategy.
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