| 1. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 2. |
- Folkersen, Lasse, et al.
(författare)
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Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
- 2017
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
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| 3. |
- 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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| 4. |
- Yang, Zhijian, et al.
(författare)
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Genetic Landscape of the ACE2 Coronavirus Receptor
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 30:SUPPL 1, s. 36-36
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Tidskriftsartikel (refereegranskat)abstract
- Background: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood.Methods: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.Results: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells.Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
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| 5. |
- Ahrentorp, Fredrik, et al.
(författare)
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Effective particle magnetic moment of multi-core particles
- 2015
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Ingår i: Journal of Magnetism and Magnetic Materials. - : Elsevier BV. - 0304-8853 .- 1873-4766. ; 380, s. 221-226
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Tidskriftsartikel (refereegranskat)abstract
- In this study we investigate the magnetic behavior of magnetic multi-core particles and the differences in the magnetic properties of multi-core and single-core nanoparticles and correlate the results with the nanostructure of the different particles as determined from transmission electron microscopy (TEM). We also investigate how the effective particle magnetic moment is coupled to the individual moments of the single-domain nanocrystals by using different measurement techniques: DC magnetometry, AC susceptometry, dynamic light scattering and TEM. We have studied two magnetic multi-core particle systems BNF Starch from Micromod with a median particle diameter of 100 am and FeraSpin R from nanoPET with a median particle diameter of 70 nm - and one single-core particle system - SHP25 from Ocean NanoTech with a median particle core diameter of 25 nm. (C) 2014 Elsevier B.V. All rights reserved.
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| 6. |
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| 7. |
- Benrick, Anna, 1979, et al.
(författare)
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A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population.
- 2008
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 189-96
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a key component in the development of atherosclerosis, and myocardial infarction (MI); therefore we investigated the association between an interleukin-6 signal transducer (IL6ST)/gp130 polymorphism, gp130 function and risk of MI. Structural modeling suggested that a non-conservative single nucleotide polymorphism in the gp130, Gly148Arg, can change the stability and functional properties of the molecule. In vitro studies were done with BAF/3 cells lacking endogenous gp130. Cells stably transfected with the gp130 148Arg variant proliferated less and showed slightly lower STAT-3 phosphorylation in response to gp130 stimulation as compared to cells transfected with gp130 148Gly. In a prospectively followed hypertensive cohort we identified 167 patients who suffered a MI during the study and compared them to matched controls (mean age 57 years, 73% males, n=482). Carriers of the 148Arg variant (f(Arg)=0.12) of the gp130 receptor had decreased odds ratio for MI in univariate analysis (0.56, 95% CI 0.34-0.91, p=0.02). In conclusion, a genetically determined structural variant of the IL-6 receptor subunit gp130 is, independently of other known risk factors, associated with decreased risk of MI. The variant is also associated with decreased IL-6 responsiveness and could lead to a configuration change in the gp130 receptor.
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| 8. |
- Bergqvist, J., et al.
(författare)
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Sub-glass transition annealing enhances polymer solar cell performance
- 2014
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Ingår i: Journal of Materials Chemistry A. - 2050-7488 .- 2050-7496. ; 2:17, s. 6146-6152
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Tidskriftsartikel (refereegranskat)abstract
- Thermal annealing of non-crystalline polymer:fullerene blends typically results in a drastic decrease in solar cell performance. In particular aggressive annealing above the glass transition temperature results in a detrimental coarsening of the blend nanostructure. We demonstrate that mild annealing below the glass transition temperature is a viable avenue to control the nanostructure of a non-crystalline thiophene–quinoxaline copolymer:fullerene blend. Direct imaging methods indicate that coarsening of the blend nanostructure can be avoided. However, a combination of absorption and luminescence spectroscopy reveals that local changes in the polymer conformation as well as limited fullerene aggregation are permitted to occur. As a result, we are able to optimise the solar cell performance evenly across different positions of the coated area, which is a necessary criterion for large-scale, high throughput production.
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| 9. |
- Biel, Anders, et al.
(författare)
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The use of MgO-paste as a biodegradeable bone cement
- 2016
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Ingår i: Materials Today. - : Elsevier. - 2214-7853. ; 3:2, s. 556-561
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Tidskriftsartikel (refereegranskat)abstract
- The use of MgO-paste as bone cement was tested on titanium cylinders implanted into rat tibia. The evaluation of bone healingwas made with the retention force (pull-out) test, light microscopy and ESEM/ EDX. Preimplantation of the MgO-paste into drillperforations of rat tibia increased the retention of the titanium implant 6-fold. The error was expressed as the 95% confidenceinterval of means (n=10 bones in each group). The observed difference between 3.46+/-0.71 N/mm2 for Ti-cylinders implantedwith MgO-paste and 0.56+/-0.26 N/mm2 for Ti-cylinders implanted directly into the bone, is statistically significant (p<0.01).The increase of retention force, caused by MgO is parallel to an increased thickness of the compact bone surrounding the implantand closer contact between bone and implant.Histological examination of the implant-related bone showed that the MgO-induced bone growth is mediated by the formation ofa bone-inducing matrix. The matrix contains organic substance, most likely proteins.
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| 10. |
- Bäcke, Olof, 1984, et al.
(författare)
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Enhanced thermal stability of a polymer solar cell blend induced by electron beam irradiation in the transmission electron microscope
- 2017
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Ingår i: Ultramicroscopy. - : Elsevier BV. - 1879-2723 .- 0304-3991. ; 173, s. 16-23
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Tidskriftsartikel (refereegranskat)abstract
- We show by in situ microscopy that the effects of electron beam irradiation during transmission electron microscopy can be used to lock microstructural features and enhance the structural thermal stability of a nanostructured polymer:fullerene blend. Polymer:fullerene bulk-heterojunction thin films show great promise for use as active layers in organic solar cells but their low thermal stability is a hindrance. Lack of thermal stability complicates manufacturing and influences the lifetime of devices. To investigate how electron irradiation affects the thermal stability of polymer:fullerene films, a model bulk-heterojunction film based on a thiophene-quinoxaline copolymer and a fullerene derivative was heat-treated in-situ in a transmission electron microscope. In areas of the film that exposed to the electron beam the nanostructure of the film remained stable, while the nanostructure in areas not exposed to the electron beam underwent large phase separation and nucleation of fullerene crystals. UV–vis spectroscopy shows that the polymer:fullerene films are stable for electron doses up to 2000 kGy.
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