| 1. |
- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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| 2. |
- Dima, Danai, et al.
(författare)
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Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years.
- 2022
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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| 3. |
- Gorski, Mathias, et al.
(författare)
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1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
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| 4. |
- Krämer, Alexander
(författare)
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Characterisation of epitope-specific B cells and the role of IgG Fc sialylation in murine arthritis models
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases are a major burden for society and economy. One of the most common autoimmune diseases is rheumatoid arthritis (RA) characterized by joint inflammation, swelling and pain. If left untreated, it ultimately leads to disability. B cells play a major role in rheumatoid arthritis as shown by numerous studies and the success of anti-CD20 B cell depletion therapy in clinical use. In healthy individuals, B cells originate and develop in the bone marrow before they exit into the periphery where they mature and differentiate. B cells act in the body in a dual role, on the one hand as professional antigen-presenting cells (APCs), taking up antigen and presenting it to cognate T cells via MHC. On the other hand, B cells can generate and mature specific antibodies against almost any given antigenic target. This diversity is achieved by a process called V(D)J recombination. V, (D) and J segments are recombined during early B cell development, creating a vast diversity of unique sequences. Subsequently, the BCR diversity can be increased even further upon B cell activation by somatic hypermutation (SHM) and class switch recombination (CSR) in the germinal center (GC) reaction. However, the stochastic process of gene rearrangement and mutations also leads to autoreactive BCRs that upon encounter of self-antigen could initiate an autoreactive immune response. This fundamental dogma of autoimmunity has been postulated in many autoimmune diseases including RA. Therefore, it is important to understand the role and regulation of self-reactive B cells in arthritis. In study I, we investigated the role of Ncf4 dependent intracellular reactive oxygen species (ROS) in controlling the differentiation from B cells into antibody-producing plasma cells. By employing Ncf4 mutated (R58A) mice we could show that lower levels of intracellular ROS induce plasma cell formation, increased CXCR3 and decreased CXCR4 expression. Increased plasma cell formation led to higher self-reactive anti-Col2 antibody production and enhanced disease severity. We concluded that intrinsic ROS can substantially modulate self-reactive B cell differentiation and thereby the disease phenotype. In study II, we mapped the pathogenic B cell epitopes on glucose-6-phosphate isomerase (GPI), an autoantigen in human RA and mouse models of arthritis. We identified a single peptide (GPI293-307) as the most dominant epitope targeted both in human and mouse models. Following the observation of the early emergence of antibodies against these epitopes, we found that GPI293-307-specific B cells are not deleted during B cell development and activated in the pathogenesis of arthritis due to encounter of a structurally modified form of GPI protein on the articular cartilage surface exposing the GPI293-307 neoepitope. We concluded that this finding has important implications about the understanding of the role of naturally existing self-reactive B cells in GPI-mediated arthritis. In study III, we studied the B cell response to Collagen type II, another important autoantigen in human RA and mouse models of arthritis. The focus was on the C1 epitope, a triple-helical peptide sequence originally identified in collagen-dependent mouse models. Using both B cell receptor knock-in mouse models, healthy human donors, and RA patients, we could identify and characterise for the first time a population of physiologically occurring self-reactive B cells that exhibit an immune-suppressive phenotype. We conclude that B suppressor cells (Bsups) represent a new subpopulation of B cells tolerizing T cells against self-antigens. Finally, in study IV, we changed the focus from the specificity of self-reactive BCRs as conferred by the Fab fragment of immunoglobulins (Igs) to the importance of the Fc fragment. More specifically, we addressed the question of the interactions between the Immunoglobulin G (IgG) isotype, its Fc glycosylation, and the consequent effector functions in different murine arthritis models. To this end, we made use of available well- characterized pathogenic monoclonal antibodies (mAbs) causing arthritis in susceptible mouse strains. A glycoengineering method was applied on these antibodies to yield an array of different glycovariants to be tested in murine models. We showed that while the Fc glycan does not play a role in the collagen antibody-induced arthritis (CAIA) model, there seems to be an isotype -/and sialylation-dependent function in the regulation of arthritis severity in the collagen-induced arthritis (CIA) model. In conclusion, we contributed towards the understanding of naturally existing autoreactive B cells in arthritis autoimmunity.
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| 5. |
- Norbury, John W., et al.
(författare)
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Are Further Cross Section Measurements Necessary for Space Radiation Protection or Ion Therapy Applications? Helium Projectiles
- 2020
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Ingår i: Frontiers in Physics. - : Frontiers Media SA. - 2296-424X. ; 8
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Forskningsöversikt (refereegranskat)abstract
- The helium ((Formula presented.) He) component of the primary particles in the galactic cosmic ray spectrum makes significant contributions to the total astronaut radiation exposure. (Formula presented.) He ions are also desirable for direct applications in ion therapy. They contribute smaller projectile fragmentation than carbon ((Formula presented.) C) ions and smaller lateral beam spreading than protons. Space radiation protection and ion therapy applications need reliable nuclear reaction models and transport codes for energetic particles in matter. Neutrons and light ions ((Formula presented.) H, (Formula presented.) H, (Formula presented.) H, (Formula presented.) He, and (Formula presented.) He) are the most important secondary particles produced in space radiation and ion therapy nuclear reactions; these particles penetrate deeply and make large contributions to dose equivalent. Since neutrons and light ions may scatter at large angles, double differential cross sections are required by transport codes that propagate radiation fields through radiation shielding and human tissue. This work will review the importance of (Formula presented.) He projectiles to space radiation and ion therapy, and outline the present status of neutron and light ion production cross section measurements and modeling, with recommendations for future needs.
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| 6. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 7. |
- Schijven, Dick, et al.
(författare)
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Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:14
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Tidskriftsartikel (refereegranskat)abstract
- Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
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| 8. |
- Xu, Zhongwei, et al.
(författare)
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A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed R69-4 inhibited neutrophil FCGR3 signaling, thereby impairing downstream IL-1β secretion and neutrophil self-orchestrated recruitment. Likewise, human isotypes of R69-4 protected against arthritis with comparable efficiency. We conclude that R69-4 abrogates autoantibody-mediated arthritis mainly by hindering FCGR3 signaling, highlighting its potential clinical utility in acute RA.
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