| 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. |
|
|
| 4. |
|
|
| 5. |
- Delp, Johannes, et al.
(författare)
-
Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors
- 2021
-
Ingår i: Archives of Toxicology. - : Springer. - 0340-5761 .- 1432-0738. ; 95:2, s. 591-615
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10-260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency.
|
|
| 6. |
- Phillips, S. P., et al.
(författare)
-
Systematic review of methods used to study the intersecting impact of sex and social locations on health outcomes
- 2020
-
Ingår i: SSM - Population Health. - : Elsevier BV. - 2352-8273. ; 12
-
Forskningsöversikt (refereegranskat)abstract
- Purpose: Independent health impacts of sex or social circumstances are well-studied, particularly among older adults. Less theorized or examined is how combinations or intersections of these underpin differential health effects. Nevertheless, and often without naming it as such, an intersectional framework aligns with studies of social determinants of health, life-course epidemiology and eco-epidemiology. In this systematic review we examined and aimed to identify research methods used to operationalize, whether intentionally or inadvertently, interconnected effects of sex and social locations on health outcomes for 45+ year olds.Methods: Using broad search terms, numerous databases, and following Prisma guidelines, 732 of 9214 papers initially identified, met inclusion criteria for full review.Results: Of the 501 papers included after full review, methods used in considering intersections of sex and social circumstances/location(s) included regression (112 of 365 papers), growth curves (7 of 22), multilevel (15 of 25), decomposition (6 of 9), mediation (10 of 17), structural equation modelling (23 of 25), and other (2 of 3). Most (n = 157) approximated intersectional analyses by including interaction terms or sex-stratifying results.Discussion: Few authors used the inherent strength of some study methods to examine intersecting traits. As even fewer began with an intersectionality framework their subsequent failure to deliver cannot be faulted, despite many studies including data and methodologies that would support intersectional analyses. There appeared to be a gap, not in analytic potential but rather in theorizing that differential distributions of social locations describe heterogeneity within the categories 'men' and 'women' that can underlie differential, gendered effects on older adults' health. While SEM, mediation and decomposition analyses emerged as particularly robust methods, the unexpected outcome was finding how few researchers consider intersectionality as a potential predictor of health.
|
|
