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| 2. |
- 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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| 3. |
- 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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| 5. |
- Darmanis, Spyros, et al.
(författare)
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Multiplexed solid-phase proximity ligation assays: Highly specific and parallel protein measurements with DNA sequencing readout
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Identification and validation of protein biomarkers is a very important step towards the understanding of the underlying mechanisms of disease, early diagnosis and efficient patient treatment. To carry out this task, methods are needed that would allow us to mine the proteome with sufficient sensitivity and specificity in large sets of samples. We present herein the development of a Multiplexed Proximity Ligation Assay (MultiPLAy), to facilitate efficient protein profiling in a parallel, sensitive and specific manner. We showed that for the simultaneous analysis of 35 proteins MultiPLAy exhibited an improved sensitivity over conventional sandwich assays as well as a smaller susceptibility to background signal increase in the transition from singleplex to multiplex. We used MultiPLAy to identify putative biomarkers in two separate sample cohorts of colorectal cancer (CRC) and cardiovascular disease (CVD) and with the use a novel multivariate analysis approach were able to identify new, as well as already known diagnostic biomarkers. Furthermore we were able to combine MultiPLAy with the use of next-generation sequencing allowing for the first time digital recording of protein profiles in blood. We demonstrated good reproducibility of MultiPLAy coupled to next-generation sequencing, as well as a satisfactory correlation to standard real-time PCR readout. We conclude that MultiPLAy has great potential as a basis for highly multiplexed protein detection assays that can be utilized for the identification of large numbers of proteins or protein variants. This will allow extensive validation of protein expression patterns in biobanked samples and in prospective studies, and can provide a much-needed platform for efficient validation of diagnostic markers for clinical use.
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| 6. |
- Jernberg, Tomas, et al.
(författare)
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Reply.
- 2004
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Annan publikation (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Lagerqvist, Bo, et al.
(författare)
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Are There Different Effects of Invasive Treatment Between Women and Men During the Acute Stage of Unstable Coronary Artery Disease?
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVES The FRISC II invasive trial compared an early invasive versus a noninvasive strategy concerning death and MI in CAD. This paper deals with the gender perspective in the same study.METHODS There were 749 women and 1708 men included in the study with a mean age of 66 and 64 years in women and men respectively. The patients were randomized to early invasive or noninvasive strategy and to placebo controlled long-term low molecular mass (1mm) heparin ( dalteparin) treatment for 3 months. Coronary angiographies were performed within the first seven days in 96 % and 10 % and revascularisation was performed within the first 10 days in 71 % and 9 % in the invasive and noninvasive groups, respectively.RESULTS Women were older but had less previous infarctions, better left ventricular function and less frequently had elevated troponin-levels. There were more patients with normal coronary arteries and less severe coronary artery lesions amongst the women. Accordingly, less interventions were performed in the female group although, among those who were revascularized, there was. no significant difference in the choice of procedure compared to men. There was no difference in the composite endpoint of MI and death at 12 months amongst women (12.4 vs. 10.5% in the invasive and non-invasive groups respectively) in contrast to the very favorable effect of the invasively treated group amongst the men (9.6 vs. 15.8%, p<0.001). In a multivariate interaction analysis there was different effect of early invasive strategy in the two genders (p=0.008)CONCLUSIONS Women with symptoms and/or signs of unstable coronary artery disease are older but still have less severe CAD and a better prognosis than men. In contrast to men, an early invasive strategy did not reduce the risk for future events amongst women. Further research is warranted to identify the most appropriate treatment strategy in women with unstable CAD.
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| 9. |
- Pol, Tymon, et al.
(författare)
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Screening of plasma biomarkers for heart failure hospitalizations and heart failure subtype in patients with atrial fibrillation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundAtrial fibrillation (AF) is associated with heart failure (HF) with a complex cause and effect relationship. We performed multiplex screening of plasma proteins to identify biomarkers and pathways associated with HF subsequent hospitalization, as well as potential pathophysiological differences between HFrEF and HFpEF at baseline in patients with AF.MethodsUsing a case-cohort design of patients with AF from the ARISTOTLE trial, the study cohort consisted of 596 cases of HF hospitalizations during follow-up and 4029 randomly selected controls without HF hospitalization. Plasma obtained at randomization was analysed with conventional immunoassays and proximity extension assay panels. Biomarker associations with HF hospitalization were evaluated using Random Survival Forest, Boruta and Cox-regression analyses. Associations between biomarkers and HF subtype were evaluated with Wilcoxon−Mann−Whitney test with Bonferroni-Holm adjustment for multiplicity.ResultsThe biomarkers most strongly associated with increased risk of HF hospitalization were NT-proBNP, BNP, cTnT‐hs, FGF-23, spon1, IGFBP-7, u-par, OPN, PTX3 and TR (all P< 0.01) and TRAP, TRAIL and GIF with lower risk. In multiplicity adjusted comparison of HFrEF versus HFpEF, levels of NT-proBNP, BNP, cTnT‐hs, renin, ACE-2, GDF-15 and IL-6 were higher in HFrEF, whereas levels of SCF and leptin were higher in HFpEF (all p<0.05).ConclusionsOut of 268 evaluated biomarkers, this study identified biomarkers representing different mechanisms strongly associated with subsequent HF hospitalization. HFrEF was more strongly associated with cardiorenal dysfunction and inflammation markers, while HFpEF was associated with adipose metabolism and tissue repair proteins.
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| 10. |
- Stenestrand, Ulf, et al.
(författare)
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New perspectives on observed variations in treatment of acute myocardial infarction between different hospitals based on multivariable analyses of a large prospective cohort
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To investigate the differences in treatment of acute myocardial infarction (AMI) between different hospitals within one country, and the causes of these differences.Method: The Register of Information and Knowledge about Swedish Heart Intensive care Admissions recorded every CCU admitted patient in 67 hospitals 1999-2000. The use often generally recommended treatments and examinations in patients with AMI were compared between the hospitals after 23 different background characteristics were encountered for by propensity score analyses.Results: 32954 primary admissions for AMI were included. After adjustment for patient characteristics there were few significant deviations between hospitals in the proportion treated with acute reperlusion, aspirin, beta-blockade or ACE-inhibition at discharge. There were, however, 3 to more than 10 fold differences between hospitals in the proportion of patients treated with intravenous B-blockers, intravenous nitroglycerin, intravenous or subcutaneous anticoagulants, and discharge lipid lowering medication and even larger discrepancies in the use of in echocardiography and coronary angiography. There was a significant (r=0.668;p<0.001) correlation between hospital average rank between the years but no correlation between hospital size and the hospital's average rank for the adjusted use of these treatments (r-0.003 and p=0.98).Conclusion: After differences between the patients background characteristics and chance findings have been taken into account, most hospitals provide similar regimens concerning treatment modalities where there is strong evidence for efficacy. The remaining large treatment variations mainly concern treatment where the indications and evidence are in development or where uncertainties remain or where there are differences in immediately available treatment facilities. In order to ascertain the quality and equality of treatment in acute myocardial infarction continuous quality control of treatments and outcomes are essential especially in areas with a rapid development of new treatments and in centres with limited resources.
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