| 1. |
- Mishra, A., et al.
(författare)
-
Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611
-
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.
|
|
| 2. |
|
|
| 3. |
- Valdes-Marquez, E., et al.
(författare)
-
Relative effects of LDL-C on ischemic stroke and coronary disease A Mendelian randomization study
- 2019
-
Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:11, s. E1176-E1187
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach. We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity. A 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 x 10(-8)). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 x 10(-3)) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 x 10(-3)) when compared with that for CHD. In contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.
|
|
| 4. |
- Young, D. R., et al.
(författare)
-
Two type Ic supernovae in low-metallicity, dwarf galaxies : diversity of explosions
- 2010
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 512, s. 70-
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: The aim of this paper is to discuss the nature of two type Ic supernovae SN 2007bg and SN 2007bi and their host galaxies. Both supernovae were discovered in wide-field, non-targeted surveys and are found to be associated with sub-luminous blue dwarf galaxies identified in SDSS images. Methods: We present BVRI photometry and optical spectroscopy of SN 2007bg and SN 2007bi and their host galaxies. Their lightcurves and spectra are compared to those of other type Ic SNe and analysis of these data provides estimates of the energetics, total ejected masses and synthesised mass of 56Ni. Detection of the host galaxy emission lines allows for metallicity measurements. Results: Neither SNe 2007bg nor 2007bi were found in association with an observed GRB, but from estimates of the metallicities of their host-galaxies they are found to inhabit similar low-metallicity environments as GRB associated supernovae. The radio-bright SN 2007bg is hosted by an extremely sub-luminous galaxy of magnitude MB = -12.4 ± 0.6 mag and an estimated oxygen abundance of 12+log(O/H) = 8.18 ± 0.17 (on the Pettini & Pagel 2004 scale). The early lightcurve evolution of SN 2007bg matches the fast-pace decline of SN 1994I giving it one of the fastest post-maximum decline rates of all broad-lined type Ic supernovae known to date and, when combined with its high expansion velocities, a high kinetic energy to ejected mass ratio (EK/Mej~2.7). We also show that SN 2007bi is possibly the most luminous type Ic known, reaching a peak magnitude of MR ~ -21.3 mag and displays a remarkably slow decline, following the radioactive decay rate of 56Co to 56Fe throughout the course of its observed lifetime. SN 2007bi also displays an extreme longevity in its spectral evolution and is still not fully nebular at approximately one year post-maximum brightness. From a simple model of the bolometric light curve of SN 2007bi we estimate a total ejected 56Ni mass of MNi = 3.5-4.5 M_ȯ, the largest 56Ni mass measured in the ejecta of a supernova to date. There are two models that could explain the high luminosity and large ejected 56Ni mass. One is a pair-instability supernova (PISN) which has been predicted to occur for massive stars at low metallicities. We measure the host galaxy metallicity of SN 2007bi to be 12+log(O/H) = 8.15 ± 0.15 (on the McGaugh 1991 scale) which is somewhat high to be consistent with the PISN model. An alternative is the core-collapse of a C+O star of 20-40 Mȯ which is the core of a star of originally 50-100 Mȯ.
|
|
