| 1. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- 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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| 4. |
- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 5. |
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| 6. |
- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 7. |
- Justice, A. E., et al.
(författare)
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Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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| 8. |
- Brown, A. G. A., et al.
(författare)
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Gaia Data Release 2 Summary of the contents and survey properties
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 616
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Tidskriftsartikel (refereegranskat)abstract
- Context. We present the second Gaia data release, Gaia DR2, consisting of astrometry, photometry, radial velocities, and information on astrophysical parameters and variability, for sources brighter than magnitude 21. In addition epoch astrometry and photometry are provided for a modest sample of minor planets in the solar system. Aims. A summary of the contents of Gaia DR2 is presented, accompanied by a discussion on the differences with respect to Gaia DR1 and an overview of the main limitations which are still present in the survey. Recommendations are made on the responsible use of Gaia DR2 results. Methods. The raw data collected with the Gaia instruments during the first 22 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into this second data release, which represents a major advance with respect to Gaia DR1 in terms of completeness, performance, and richness of the data products. Results. Gaia DR2 contains celestial positions and the apparent brightness in G for approximately 1.7 billion sources. For 1.3 billion of those sources, parallaxes and proper motions are in addition available. The sample of sources for which variability information is provided is expanded to 0 : 5 million stars. This data release contains four new elements: broad-band colour information in the form of the apparent brightness in the G(BP) (330-680 nm) and G(RP) (630-1050 nm) bands is available for 1.4 billion sources; median radial velocities for some 7 million sources are presented; for between 77 and 161 million sources estimates are provided of the stellar effective temperature, extinction, reddening, and radius and luminosity; and for a pre-selected list of 14 000 minor planets in the solar system epoch astrometry and photometry are presented. Finally, Gaia DR2 also represents a new materialisation of the celestial reference frame in the optical, the Gaia-CRF2, which is the first optical reference frame based solely on extragalactic sources. There are notable changes in the photometric system and the catalogue source list with respect to Gaia DR1, and we stress the need to consider the two data releases as independent. Conclusions. Gaia DR2 represents a major achievement for the Gaia mission, delivering on the long standing promise to provide parallaxes and proper motions for over 1 billion stars, and representing a first step in the availability of complementary radial velocity and source astrophysical information for a sample of stars in the Gaia survey which covers a very substantial fraction of the volume of our galaxy.
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| 9. |
- Katz, D., et al.
(författare)
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Gaia Data Release 2 Mapping the Milky Way disc kinematics
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 616
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Tidskriftsartikel (refereegranskat)abstract
- Context. The second Gaia data release (Gaia DR2) contains high-precision positions, parallaxes, and proper motions for 1.3 billion sources as well as line-of-sight velocities for 7.2 million stars brighter than G(RVS) = 12 mag. Both samples provide a full sky coverage. Aims. To illustrate the potential of Gaia DR2, we provide a first look at the kinematics of the Milky Way disc, within a radius of several kiloparsecs around the Sun. Methods. We benefit for the first time from a sample of 6.4 million F-G-K stars with full 6D phase-space coordinates, precise parallaxes (sigma((omega) over bar)/(omega) over bar <= 20%), and precise Galactic cylindrical velocities (median uncertainties of 0.9-1.4 km s(-1) and 20% of the stars with uncertainties smaller than 1 km s(-1) on all three components). From this sample, we extracted a sub-sample of 3.2 million giant stars to map the velocity field of the Galactic disc from similar to 5 kpc to similar to 13 kpc from the Galactic centre and up to 2 kpc above and below the plane. We also study the distribution of 0.3 million solar neighbourhood stars (r < 200 pc), with median velocity uncertainties of 0.4 km s(-1), in velocity space and use the full sample to examine how the over-densities evolve in more distant regions. Results. Gaia DR2 allows us to draw 3D maps of the Galactocentric median velocities and velocity dispersions with unprecedented accuracy, precision, and spatial resolution. The maps show the complexity and richness of the velocity field of the galactic disc. We observe streaming motions in all the components of the velocities as well as patterns in the velocity dispersions. For example, we confirm the previously reported negative and positive galactocentric radial velocity gradients in the inner and outer disc, respectively. Here, we see them as part of a non-axisymmetric kinematic oscillation, and we map its azimuthal and vertical behaviour. We also witness a new global arrangement of stars in the velocity plane of the solar neighbourhood and in distant regions in which stars are organised in thin substructures with the shape of circular arches that are oriented approximately along the horizontal direction in the U - V plane. Moreover, in distant regions, we see variations in the velocity substructures more clearly than ever before, in particular, variations in the velocity of the Hercules stream. Conclusions. Gaia DR2 provides the largest existing full 6D phase-space coordinates catalogue. It also vastly increases the number of available distances and transverse velocities with respect to Gaia DR1. Gaia DR2 offers a great wealth of information on the Milky Way and reveals clear non-axisymmetric kinematic signatures within the Galactic disc, for instance. It is now up to the astronomical community to explore its full potential.
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| 10. |
- Spoto, F., et al.
(författare)
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Gaia Data Release 2 : Observations of solar system objects
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 616
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Tidskriftsartikel (refereegranskat)abstract
- Context: The Gaia spacecraft of the European Space Agency (ESA) has been securing observations of solar system objects (SSOs) since the beginning of its operations. Data Release 2 (DR2) contains the observations of a selected sample of 14,099 SSOs. These asteroids have been already identified and have been numbered by the Minor Planet Center repository. Positions are provided for each Gaia observation at CCD level. As additional information, complementary to astrometry, the apparent brightness of SSOs in the unfiltered G band is also provided for selected observations.Aims: We explain the processing of SSO data, and describe the criteria we used to select the sample published in Gaia DR2. We then explore the data set to assess its quality.Methods: To exploit the main data product for the solar system in Gaia DR2, which is the epoch astrometry of asteroids, it is necessary to take into account the unusual properties of the uncertainty, as the position information is nearly one-dimensional. When this aspect is handled appropriately, an orbit fit can be obtained with post-fit residuals that are overall consistent with the a-priori error model that was used to define individual values of the astrometric uncertainty. The role of both random and systematic errors is described. The distribution of residuals allowed us to identify possible contaminants in the data set (such as stars). Photometry in the G band was compared to computed values from reference asteroid shapes and to the flux registered at the corresponding epochs by the red and blue photometers (RP and BP).Results: The overall astrometric performance is close to the expectations, with an optimal range of brightness G similar to 12 - 17. In this range, the typical transit-level accuracy is well below 1 mas. For fainter asteroids, the growing photon noise deteriorates the performance. Asteroids brighter than G similar to 12 are affected by a lower performance of the processing of their signals. The dramatic improvement brought by Gaia DR2 astrometry of SSOs is demonstrated by comparisons to the archive data and by preliminary tests on the detection of subtle non-gravitational effects.
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