| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 3. |
- Artaxo, Paulo, et al.
(författare)
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Tropical and Boreal Forest – Atmosphere Interactions : A Review
- 2022
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Ingår i: Tellus. Series B, Chemical and physical meteorology. - : Stockholm University Press. - 0280-6509 .- 1600-0889. ; 74:1, s. 24-163
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Forskningsöversikt (refereegranskat)abstract
- This review presents how the boreal and the tropical forests affect the atmosphere, its chemical composition, its function, and further how that affects the climate and, in return, the ecosystems through feedback processes. Observations from key tower sites standing out due to their long-term comprehensive observations: The Amazon Tall Tower Observatory in Central Amazonia, the Zotino Tall Tower Observatory in Siberia, and the Station to Measure Ecosystem-Atmosphere Relations at Hyytiäla in Finland. The review is complemented by short-term observations from networks and large experiments.The review discusses atmospheric chemistry observations, aerosol formation and processing, physiochemical aerosol, and cloud condensation nuclei properties and finds surprising similarities and important differences in the two ecosystems. The aerosol concentrations and chemistry are similar, particularly concerning the main chemical components, both dominated by an organic fraction, while the boreal ecosystem has generally higher concentrations of inorganics, due to higher influence of long-range transported air pollution. The emissions of biogenic volatile organic compounds are dominated by isoprene and monoterpene in the tropical and boreal regions, respectively, being the main precursors of the organic aerosol fraction.Observations and modeling studies show that climate change and deforestation affect the ecosystems such that the carbon and hydrological cycles in Amazonia are changing to carbon neutrality and affect precipitation downwind. In Africa, the tropical forests are so far maintaining their carbon sink.It is urgent to better understand the interaction between these major ecosystems, the atmosphere, and climate, which calls for more observation sites, providing long-term data on water, carbon, and other biogeochemical cycles. This is essential in finding a sustainable balance between forest preservation and reforestation versus a potential increase in food production and biofuels, which are critical in maintaining ecosystem services and global climate stability. Reducing global warming and deforestation is vital for tropical forests.
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| 4. |
- Binder, Zev A., et al.
(författare)
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Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development
- 2018
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 34:1, s. 163-177
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Tidskriftsartikel (refereegranskat)abstract
- We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR(A289D/T/V)). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR(A289D/T/V) mutants, corroborated in mice bearing intracranial tumors expressing EGFR(A289V) and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR(A289V) tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR(A289V) mutation in glioblastoma, postulating EGFR(A289V) as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.
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| 7. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 8. |
- Divé, Iris, et al.
(författare)
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Tick-borne encephalitis virus (TBEV) infection in pregnancy: Absence of virus transmission to the fetuses despite severe maternal disease - A case study.
- 2020
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Ingår i: Ticks and tick-borne diseases. - : Elsevier BV. - 1877-9603 .- 1877-959X. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Tick-borne encephalitis (TBE) is an emerging infectious disease in large parts of Europe and Asia. Whereas other members of the Flaviviridae family can harm fetal development, there are only very few reports on TBE virus (TBEV) infections during pregnancy. Thus, the implications for fetal health remain largely unknown. In this study, we present detailed pre- and postnatal health assessment of three children in the context of severe maternal TBEV infection during pregnancy. Following acute TBEV infection of the mothers, intrauterine growth and development of all children were assessed by repetitive prenatal ultrasound. Postnatal examinations included clinical and virological analyses over a follow-up period of 18 months. Prenatally, no signs of intrauterine growth restrictions were observed. All neonates were delivered at term. Umbilical cord blood of the newborns tested negative for TBEV RNA. Virus-specific IgG antibodies were positive at birth but negative at 9 and 11 months of age. Importantly, IgM antibodies remained negative throughout the period of observation. Taken together, these clinical and virological data strongly suggest that fetal TBEV infection did not occur, despite severe manifestations in the mothers.
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| 9. |
- Kaidar-Person, Orit, et al.
(författare)
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The Lucerne Toolbox 2 to optimise axillary management for early breast cancer : a multidisciplinary expert consensus
- 2023
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Ingår i: EClinicalMedicine. - 2589-5370. ; 61
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Forskningsöversikt (refereegranskat)abstract
- Clinical axillary lymph node management in early breast cancer has evolved from being merely an aspect of surgical management and now includes the entire multidisciplinary team. The second edition of the “Lucerne Toolbox”, a multidisciplinary consortium of European cancer societies and patient representatives, addresses the challenges of clinical axillary lymph node management, from diagnosis to local therapy of the axilla. Five working packages were developed, following the patients’ journey and addressing specific clinical scenarios. Panellists voted on 72 statements, reaching consensus (agreement of 75% or more) in 52.8%, majority (51%–74% agreement) in 43.1%, and no decision in 4.2%. Based on the votes, targeted imaging and standardized pathology of lymph nodes should be a prerequisite to planning local and systemic therapy, axillary lymph node dissection can be replaced by sentinel lymph node biopsy ( ± targeted approaches) in a majority of scenarios; and positive patient outcomes should be driven by both low recurrence risks and low rates of lymphoedema.
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| 10. |
- Mahler, Jasmin, et al.
(författare)
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Endogenous murine A beta increases amyloid deposition in APP23 but not in APPPS1 transgenic mice
- 2015
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 36:7, s. 2241-2247
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Tidskriftsartikel (refereegranskat)abstract
- Endogenous murine amyloid-beta peptide (A beta) is expressed in most A beta precursor protein (APP) transgenic mouse models of Alzheimers disease but its contribution to beta-amyloidosis remains unclear. We demonstrate similar to 35% increased cerebral A beta load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster A beta-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine A beta, and immunoelectron microscopy revealed a tight association of murine A beta with human A beta fibrils. Deposition of murine A beta was considerably less efficient compared with the deposition of human A beta indicating a lower amyloidogenic potential of murine A beta in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human A beta and deposits of mixed human-murine A beta. Our data demonstrate a differential effect of murine A beta on human A beta deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse A beta may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.
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