| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
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| 3. |
- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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| 4. |
- Aragam, KG, et al.
(författare)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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| 5. |
- Aragam, KG, et al.
(författare)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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| 6. |
- Lazar, Tamas, et al.
(författare)
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PED in 2021 : A major update of the protein ensemble database for intrinsically disordered proteins
- 2021
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 49:D1, s. 404-411
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Tidskriftsartikel (refereegranskat)abstract
- The Protein Ensemble Database (PED) (https://proteinensemble.org), which holds structural ensembles of intrinsically disordered proteins (IDPs), has been significantly updated and upgraded since its last release in 2016. The new version, PED 4.0, has been completely redesigned and reimplemented with cutting-edge technology and now holds about six times more data (162 versus 24 entries and 242 versus 60 structural ensembles) and a broader representation of state of the art ensemble generation methods than the previous version. The database has a completely renewed graphical interface with an interactive feature viewer for region-based annotations, and provides a series of descriptors of the qualitative and quantitative properties of the ensembles. High quality of the data is guaranteed by a new submission process, which combines both automatic and manual evaluation steps. A team of biocurators integrate structured metadata describing the ensemble generation methodology, experimental constraints and conditions. A new search engine allows the user to build advanced queries and search all entry fields including cross-references to IDP-related resources such as DisProt, MobiDB, BMRB and SASBDB. We expect that the renewed PED will be useful for researchers interested in the atomic-level understanding of IDP function, and promote the rational, structure-based design of IDP-targeting drugs.
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| 7. |
- Carnicelli, Anthony P, et al.
(författare)
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Individual Patient Data from the Pivotal Randomized Controlled Trials of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (COMBINE AF) : Design and Rationale
- 2021
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Ingår i: American Heart Journal. - : Elsevier. - 0002-8703 .- 1097-6744. ; Mar:233, s. 48-58
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date.DESIGN: COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771).CONCLUSIONS: In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.
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| 8. |
- Draycott, T., et al.
(författare)
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Reduction in resource use with the misoprostol vaginal insert vs the dinoprostone vaginal insert for labour induction: a model-based analysis from a United Kingdom healthcare perspective
- 2016
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Ingår i: BMC Health Services Research. - : BIOMED CENTRAL LTD. - 1472-6963. ; 16:1, s. 49-
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Tidskriftsartikel (refereegranskat)abstract
- Background: In view of the increasing pressure on the UKs maternity units, new methods of labour induction are required to alleviate the burden on the National Health Service, while maintaining the quality of care for women during delivery. A model was developed to evaluate the resource use associated with misoprostol vaginal inserts (MVIs) and dinoprostone vaginal inserts (DVIs) for the induction of labour at term. Methods: The one-year Markov model estimated clinical outcomes in a hypothetical cohort of 1397 pregnant women (parous and nulliparous) induced with either MVI or DVI at Southmead Hospital, Bristol, UK. Efficacy and safety data were based on published and unpublished results from a phase III, double-blind, multicentre, randomised controlled trial. Resource use was modelled using data from labour induction during antenatal admission to patient discharge from Southmead Hospital. The models sensitivity to key parameters was explored in deterministic multi-way and scenario-based analyses. Results: Over one year, the model results indicated MVI use could lead to a reduction of 10,201 h (28.9 %) in the time to vaginal delivery, and an increase of 121 % and 52 % in the proportion of women achieving vaginal delivery at 12 and 24 h, respectively, compared with DVI use. Inducing women with the MVI could lead to a 25.2 % reduction in the number of midwife shifts spent managing labour induction and 451 fewer hospital bed days. These resource utilisation reductions may equate to a potential 27.4 % increase in birthing capacity at Southmead Hospital, when using the MVI instead of the DVI. Conclusions: Resource use, in addition to clinical considerations, should be considered when making decisions about labour induction methods. Our model analysis suggests the MVI is an effective method for labour induction, and could lead to a considerable reduction in resource use compared with the DVI, thereby alleviating the increasing burden of labour induction in UK hospitals.
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| 9. |
- Glawion, S., et al.
(författare)
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Two-Spinon and Orbital Excitations of the Spin-Peierls System TiOCl
- 2011
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 107:10, s. 107402-
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Tidskriftsartikel (refereegranskat)abstract
- We combine high-resolution resonant inelastic x-ray scattering with cluster calculations utilizing a recently derived effective magnetic scattering operator to analyze the polarization, excitation energy, and momentum-dependent excitation spectrum of the low-dimensional quantum magnet TiOCl in the range expected for orbital and magnetic excitations (0-2.5 eV). Ti 3d orbital excitations yield complete information on the temperature-dependent crystal-field splitting. In the spin-Peierls phase we observe a dispersive two-spinon excitation and estimate the inter- and intradimer magnetic exchange coupling from a comparison to cluster calculations.
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| 11. |
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| 12. |
- Ståhlberg, Anders, 1975, et al.
(författare)
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Normal and Functional TP53 in Genetically Stable Myxoid/Round Cell Liposarcoma
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid/round-cell liposarcoma (MLS/RCLS) is characterized by either the fusion gene FUS-DDIT3 or the less commonly occurring EWSR1-DDIT3 and most cases carry few or no additional cytogenetic changes. There are conflicting reports concerning the status and role of TP53 in MLS/RCLS. Here we analysed four MLS/RCLS derived cell lines for TP53 mutations, expression and function. Three SV40 transformed cell lines expressed normal TP53 proteins. Irradiation caused normal posttranslational modifications of TP53 and induced P21 expression in two of these cell lines. Transfection experiments showed that the FUS-DDIT3 fusion protein had no effects on irradiation induced TP53 responses. Ion Torrent AmpliSeq screening, using the Cancer Hotspot panel, showed no dysfunctional or disease associated alleles/mutations. In conclusion, our results suggest that most MLS/RCLS cases carry functional TP53 genes and this is consistent with the low numbers of secondary mutations observed in this tumor entity.
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| 13. |
- Szidat, S, et al.
(författare)
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Fossil and non-fossil sources of organic carbon (OC) and elemental carbon (EC) in Goteborg, Sweden
- 2008
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Ingår i: Atmos. Chem. Phys. Discuss.. ; 8, s. 16255-16289
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Particulate matter was collected at an urban site in G¨oteborg (Sweden) in February/ March 2005 and in June/July 2006. Additional samples were collected at a rural site for the winter period. Elemental carbon (EC), organic carbon (OC), water-insoluble OC (WINSOC), and water-soluble OC (WSOC) were analyzed for 14C in order to distinguish fossil from non-fossil emissions. As wood burning is the single major source of non-fossil EC, its contribution can be quantified directly. For non-fossil OC, the wood burning fraction was determined independently by levoglucosan and 14C analysis and combined using Latin-hypercube sampling (LHS). For the winter period, the relative contribution of EC from wood burning to the total EC was >3 times higher at the rural site compared to the urban site, whereas the absolute concentrations of EC from wood burning were comparable at both sites. Thus, the urban site is substantially more influenced by fossil EC emissions. For summer, biogenic emissions dominated OC concentrations most likely due to secondary organic aerosol (SOA) formation. During both seasons, a more pronounced fossil signal was observed for Go¨teborg than has previously been reported for Zurich, Switzerland. Analysis of air mass origin using back trajectories suggests that the fossil impact was larger when local sources dominated, whereas long-range transport caused an enhanced non-fossil signal. In comparison to other European locations, concentrations of levoglucosan and other monosaccharide anhydrides were low for the urban and the rural site in the area of Go¨teborg during winter. The comparison of summer and winter results provides insight into the annual cycle of anthropogenic vs. biogenic contributions to the atmospheric aerosol.
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| 14. |
- Szidat, S., et al.
(författare)
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Fossil and non-fossil sources of organic carbon (OC) and elemental carbon (EC) in Göteborg, Sweden
- 2009
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 9:5, s. 1521-1535
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Tidskriftsartikel (refereegranskat)abstract
- Particulate matter was collected at an urban site in Göteborg (Sweden) in February/March 2005 and in June/July 2006. Additional samples were collected at a rural site for the winter period. Total carbon (TC) concentrations were 2.1–3.6μgm−3, 1.8–1.9μgm−3, and 2.2– 3.0μgm−3 for urban/winter, rural/winter, and urban/summer conditions, respectively. Elemental carbon (EC), organic carbon (OC), water-insoluble OC (WINSOC), and watersoluble OC (WSOC) were analyzed for 14C in order to distinguish fossil from non-fossil emissions. As wood burning is the single major source of non-fossil EC, its contribution can be quantified directly. For non-fossil OC, the wood-burning fraction was determined independently by levoglucosan and 14C analysis and combined using Latin-hypercube sampling (LHS). For the winter period, the relative contribution of EC from wood burning to the total EC was >3 times higher at the rural site compared to the urban site, whereas the absolute concentrations of EC from wood burning were elevated only moderately at the rural compared to the urban site. Thus, the urban site is substantially more influenced by fossil EC emissions. For summer, biogenic emissions dominated OC concentrations most likely due to secondary organic aerosol(SOA) formation. During both seasons, a more pronounced fossil signal was observed for G¨oteborg than has previously been reported for Zurich, Switzerland. Analysis of air mass origin using back trajectories suggests that the fossil impact was larger when local sources dominated, whereas longrange transport caused an enhanced non-fossil signal. In comparison to other European locations, concentrations of levoglucosan and other monosaccharide anhydrides were low for the urban and the rural site in the area of G¨oteborg during winter.
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| 15. |
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