| 1. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 2. |
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| 3. |
- 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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| 8. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 9. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 10. |
- Williamson, Alice, et al.
(författare)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Tidskriftsartikel (refereegranskat)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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| 11. |
- Hrovat, B., et al.
(författare)
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Preparation of synthetic micro- and nano plastics for method validation studies
- 2024
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 925
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Tidskriftsartikel (refereegranskat)abstract
- Microplastic (MP) pollution is a persisting global problem. Accurate analysis is essential in quantifying the effects of microplastic pollution and develop novel technologies that reliably and reproducibly measure microplastic content in various samples. The most common methods for this are FTIR and Raman spectroscopy. Coloured, standardized beads are often used for method validation tests, which limits the conclusions to a very specific case rarely observed in the natural environment. This study focuses on the preparation of reference micro- and nanoplastics via cryogenic milling and shows their use for FTIR and Raman method validation studies. MPs can now be reproducibly milled from various plastics, offering the advantages of a better representation of MPs in real environment. Moreover, this study highlights issues with the current detection methods, up to now considered as the most reliable ones for MP detection and identification. Such issues, e.g. misidentification, will need to be addressed in the future. Additionally, milled MPs were used in experiments with commercial high-resolution imaging device, enabling a possible in-situ optical detection of microplastics. These experiments represent a step forward in understanding MPs in a water sample and provide a basis for a more accurate detection and identification directly from water, which would considerably reduce the time of analysis.
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| 16. |
- Kortesniemi, Maaria, et al.
(författare)
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Nutritional metabolomics: Recent developments and future needs
- 2023
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Ingår i: Current Opinion in Chemical Biology. - 1879-0402 .- 1367-5931. ; 77
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Forskningsöversikt (refereegranskat)abstract
- Metabolomics has rapidly been adopted as one of the key methods in nutrition research. This review focuses on the recent developments and updates in the field, including the analytical methodologies that encompass improved instrument sensitivity, sampling techniques and data integration (multiomics). Metabolomics has advanced the discovery and validation of dietary biomarkers and their implementation in health research. Metabolomics has come to play an important role in the understanding of the role of small molecules resulting from the diet–microbiota interactions when gut microbiota research has shifted towards improving the understanding of the activity and functionality of gut microbiota rather than composition alone. Currently, metabolomics plays an emerging role in precision nutrition and the recent developments therein are discussed.
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| 17. |
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| 18. |
- Kumar, Amit, et al.
(författare)
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Astroglial tracer BU99008 detects multiple binding sites in Alzheimer's disease brain
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:10, s. 5833-5847
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Tidskriftsartikel (refereegranskat)abstract
- With reactive astrogliosis being established as one of the hallmarks of Alzheimer’s disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.
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| 19. |
- Low, Dorrain Yanwen, et al.
(författare)
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Data sharing in PredRet for accurate prediction of retention time: Application to plant food bioactive compounds
- 2021
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Ingår i: Food Chemistry. - : Elsevier BV. - 0308-8146 .- 1873-7072. ; 357
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Tidskriftsartikel (refereegranskat)abstract
- Prediction of retention times (RTs) is increasingly considered in untargeted metabolomics to complement MS/MS matching for annotation of unidentified peaks. We tested the performance of PredRet (http://predret.org/) to predict RTs for plant food bioactive metabolites in a data sharing initiative containing entry sets of 29–103 compounds (totalling 467 compounds, >30 families) across 24 chromatographic systems (CSs). Between 27 and 667 predictions were obtained with a median prediction error of 0.03–0.76 min and interval width of 0.33–8.78 min. An external validation test of eight CSs showed high prediction accuracy. RT prediction was dependent on shape and type of LC gradient, and number of commonly measured compounds. Our study highlights PredRet's accuracy and ability to transpose RT data acquired from one CS to another CS. We recommend extensive RT data sharing in PredRet by the community interested in plant food bioactive metabolites to achieve a powerful community-driven open-access tool for metabolomics annotation.
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| 20. |
- Mubanga, M, et al.
(författare)
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The gut microbiome and asthma in a Swedish twin study
- 2023
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Ingår i: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. - 1365-2222. ; 53:11, s. 1212-1215
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 21. |
- Mubanga, M, et al.
(författare)
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The gut microbiome and asthma in a Swedish twin study
- 2023
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Ingår i: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. - 1365-2222.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 22. |
- Peiponen, K. -E, et al.
(författare)
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Sorting microplastics from other materials in water samples by ultra-high-definition imaging
- 2023
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Ingår i: Journal of the European Optical Society-Rapid Publications. - : EDP Sciences. - 1990-2573. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- In this study a commercial particle analyzer was used to image and help sorting microplastic particles (MPs) dispersed in filtrated and de-aerated tap water. The device provides a relatively easy and fast procedure for obtaining ultra-high-definition imaging, allowing the determination of shape, size, and number of 2D-projections of solid particles. The image analysis revealed clear differences among the studied different MPs originating from the grinding of five common grades of plastic sheets as they affect the image rendering differently, principally due to the light scattering either at the surface or in the volume of the microplastics. The high-quality imaging of the device also allows the discrimination of the microplastics from air bubbles with well-defined spherical shapes as well as to obtain an estimate of the size of MPs in a snapshot. We associate the differences among the shapes of the identified MPs in this study depending on the plastic type with known physical properties, such as brittleness, crystallinity, or softness. Furthermore, as a novel method we exploit a parameter based on the light intensity map from moving particles in cuvette flow to sort MPs from other particles, such as, wood fiber, human hair, and air bubbles. Using the light intensity map, which is related to the plastic-water refractive index ratio, the presence of microplastics in water can be revealed among other particles, but not their specific plastic type.
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| 23. |
- Revol, Rebecca, et al.
(författare)
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Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair
- 2023
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Ingår i: Molecular and Cellular Neuroscience. - 1044-7431 .- 1095-9327. ; 127
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Tidskriftsartikel (refereegranskat)abstract
- Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-beta precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following beta and gamma-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription. In this study, we investigated if Fe65 nuclear localization can also be regulated by different alpha-secretases, also known to participate in RIP of APP and other transmembrane proteins. We found that in both Phorbol 12-myristate 13-acetate and all-trans retinoic acid differentiated neuroblastoma cells a strong negative impact on Fe65 nuclear localization, equal to the effect observed upon gamma-secretase inhibition, could be detected following inhibition of all three (ADAM9, ADAM10 and ADAM17) alpha-secretases. Moreover, using the comet assay and analysis of Fe65 dependent DNA repair associated posttranslational modifications of histones, we could show that inhibition of alpha-secretase-mediated Fe65 nuclear translocation resulted in impaired capacity of the cells to repair DNA damage. Taken together this suggests that alpha-secretase processing of APP and/or other Fe65 interacting transmembrane proteins play an important role in regulating Fe65 nuclear translocation and DNA repair.
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| 24. |
- Vitale, Marilena, et al.
(författare)
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Putative metabolites involved in the beneficial effects of wholegrain cereal: Nontargeted metabolite profiling approach
- 2021
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Ingår i: Nutrition, Metabolism and Cardiovascular Diseases. - : Elsevier BV. - 0939-4753 .- 1590-3729. ; 31:4, s. 1156-1165
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Wholegrain cereals have been implicated in the reduction of lifestyle-related chronic diseases risk including cardiovascular diseases and type 2 diabetes. Molecular mechanisms responsible for the beneficial health effects are not entirely understood. The aims of this study were 1) to identify new potential plasma biomarker candidate metabolites of wholegrain cereal foods intake and 2) to examine whether some putative metabolites associated with wholegrain foods intake may play a role in the improvement of cardiometabolic risk factors. Methods and results: Analysis have been conducted in 54 individuals with metabolic syndrome of both genders, age 40–65 years, randomly assigned to 2 dietary interventions lasting 12-week: 1) wholegrain enriched diet (n = 28), and 2) refined-wheat cereals diet (control diet) (n = 26). Nontargeted metabolite profiling analysis was performed on fasting plasma samples collected at baseline and at the end of the experimental diets. Our data show that, at the end of the intervention, a higher intake of wholegrain (tertile 3) was significantly associated with a marked increase in several lipid compounds, as PC (20:4/16:1), LPC (20:4), LPC (22:6), LPC (18:3), LPC (22:5), and a phenolic compound (P < .05 for all). In the wholegrain group, higher concentrations of these metabolites (tertile 3 vs tertile 1 of each metabolite) were significantly associated with lower postprandial insulin and triglyceride responses (P < .05) by 29% and 37%, respectively. Conclusion: These observations suggest a possible role of lipid and polyphenol metabolites in the postprandial metabolic benefits of wholegrains in subjects at high risk of cardiovascular disease. In addition, they provide insight into the role of these metabolites as potential candidate biomarkers of wholegrain foods. The study was registered on ClinicalTrials.gov (identifier: NCT00945854).
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