| 1. |
- Elmér, Evelina, et al.
(författare)
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Increased Frequencies of Switched Memory B Cells and Plasmablasts in Peripheral Blood from Patients with ANCA-Associated Vasculitis
- 2020
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Ingår i: Journal of Immunology Research. - : Hindawi Limited. - 2314-7156 .- 2314-8861. ; 2020
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Tidskriftsartikel (refereegranskat)abstract
- B cells are thought to play a central role in the pathogenesis of antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV). ANCAs have been proposed to cause vasculitis by activating primed neutrophils to damage small blood vessels. We studied a cohort of AAV patients of which a majority were in remission and diagnosed with granulomatosis with polyangiitis (GPA). Using flow cytometry, the frequencies of CD19+ B cells and subsets in peripheral blood from 106 patients with AAV and 134 healthy controls were assessed. B cells were divided into naive, preswitch memory, switched memory, and exhausted memory cells. Naive and switched memory cells were further subdivided into transitional cells and plasmablasts, respectively. In addition, serum concentrations of immunoglobulin A, G, and M were measured and clinical data were retrieved. AAV patients displayed, in relation to healthy controls, a decreased frequency of B cells of lymphocytes (5.1% vs. 8.3%) and total B cell number. For the subsets, a decrease in percentage of transitional B cells (0.7% vs. 4.4%) and expansions of switched memory B cells (22.3% vs. 16.5%) and plasmablasts (0.9% vs. 0.3%) were seen. A higher proportion of B cells was activated (CD95+) in patients (20.6% vs. 10.3%), and immunoglobulin levels were largely unaltered. No differences in B cell frequencies between patients in active disease and remission were observed. Patients in remission with a tendency to relapse had, compared to nonrelapsing patients, decreased frequencies of B cells (3.5% vs. 6.5%) and transitional B cells (0.1% vs. 1.1%) and an increased frequency of activated exhausted memory B cells (30.8% vs. 22.3%). AAV patients exhibit specific changes in frequencies of CD19+ B cells and their subsets in peripheral blood. These alterations could contribute to the autoantibody-driven inflammatory process in AAV.
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| 2. |
- Graff, M., et al.
(författare)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 3. |
- Hellmark, Thomas, et al.
(författare)
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Eosinophils in anti-neutrophil cytoplasmic antibody associated vasculitis
- 2019
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Ingår i: BMC Rheumatology. - : Springer Science and Business Media LLC. - 2520-1026. ; 3:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Anti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) are characterized by autoimmune small vessel inflammation. Eosinophils are multifunctional cells with both pro-inflammatory and immunoregulatory properties. Tissue activated eosinophils secrete cyto- and chemokines and form extracellular traps (EETs), they release free granules and produce reactive oxygen species. The role of eosinophils is well established in eosinophilic granulomatosis with polyangiitis (EGPA) but very little is known about their role in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).Methods: The expression of surface markers CD11c, CD11b, CD16, CD35, CD62L, CD64, CD88, Siglec-8 and CD193 and reactive oxygen species production by peripheral blood eosinophils were studied using flow cytometry. Fluorescence microscopy was used to visualize the release of eosinophil extracellular DNA traps (EETs). 98 GPA and MPA patients and 121 healthy controls were included in the study.Results: Both GPA and MPA patients had decreased frequency of eosinophils in peripheral blood compared with healthy controls (p < 0.0001), which could not solely be explained by corticosteroid treatment. The patient's eosinophils showed increased surface expression of the Fc receptors CD16 (p < 0.0001) and CD64 (p = 0.0035) as well as CCR3 (CD193) (p = 0.0022). Decreased expression was found of the complement receptors CD35 (p = 0.0022), CD88 (p < 0,0001) as well as CD11c (p < 0,0001), CD11b (p = 0.0061) and Siglec-8 (p = 0,0015). Moreover, GPA and MPA eosinophils, showed decreased capacity to produce ROS (p < 0.0001). ANCA stimulation of eosinophils from GPA and MPA patients after C5a priming enhanced EETosis (p = 0,0088).Conclusions: The percentage of eosinophils were decreased in peripheral blood in GPA and MPA patients and showed altered surface marker expression and function. The enhanced EETosis after ANCA stimulation, suggests that eosinophil can contribute to the autoantibody driven inflammatory process.
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| 4. |
- Johansson, Åsa Cm, et al.
(författare)
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Impaired phagocytosis and reactive oxygen species production in phagocytes is associated with systemic vasculitis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Anti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) is a group of autoimmune diseases, characterized by small vessel inflammation. Phagocytes such as neutrophils and monocytes are the main effector cells found around the inflamed vessel wall. Therefore, we wanted to investigate aspects of function and activation of these cells in patients with AAV.METHODS: Flow cytometry was used to evaluate: the expression of activation markers (CD11c, CD62L, CD177 and C5aR); the number of recently released neutrophils from bone marrow, defined as CD10(-)D16(low) cells in peripheral blood; and the capacity of peripheral blood monocytes and polymorphonuclear leukocytes (PMN) to produce reactive oxygen species and to phagocytose opsonized bacteria.RESULTS: AAV patients (n = 104) showed an increase of CD10(-)CD16(low) neutrophils and total PMN in peripheral blood, suggesting a combination of increased bone marrow release and prolonged survival. An increased percentage of AAV PMN expressed CD177 but no other signs of activation were seen. A decreased production of reactive oxygen species was observed in AAV phagocytes, which was associated with disease activity. Moreover, granulocytes from patients with microscopic polyangiitis showed lower oxidative burst capacity compared to patients with granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis. In addition, decreased phagocytosis capacity was seen in PMN and monocytes.CONCLUSION: Our results indicate that phagocytes from AAV patients have impaired function, are easily mobilized from bone marrow but are not particularly activated. The association between low reactive oxygen species formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor.
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| 5. |
- Lilliebladh, Sandra, et al.
(författare)
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Phenotypic Characterization of Circulating CD4+ T Cells in ANCA-Associated Vasculitis
- 2018
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Ingår i: Journal of Immunology Research. - : Hindawi Limited. - 2314-7156 .- 2314-8861. ; 2018
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Tidskriftsartikel (refereegranskat)abstract
- T cell-mediated immune responses are thought to play an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody- (ANCA-) associated vasculitides (AAV). CD4+ T cells can be divided into subsets depending on their expression of chemokine receptors. In this study, different CD4+ T cell populations in patients with AAV were analysed and compared to healthy blood donors as well as therapy controls. 18 patients with active AAV, 46 in remission, 21 healthy controls (HBD), and 15 therapy controls (TC) were enrolled. CD4+ T cells were divided into Th1, Th2, and Th17 cells and further subdivided into naïve, central memory, effector memory, and effector cells. Regulatory T cells were also analysed. Concentrations of cytokines and chemokines produced by the respective CD4+ T cell subset in plasma from 33 of the patients were measured by ELISA and compared to HBD. Clinical data were collected on all patients. CCL20 concentrations and percentages of Th17 cells (p = 0.019) were elevated in AAV patients compared to HBD. AAV patients had lower percentages of naïve CD4+ T cells (p = 0.0016) and a corresponding increase in proportion of effector memory CD4+ T cells when comparing to HBD (p = 0.027). Therapy controls showed similar results as AAV patients. In this study, we found that CD4+ T cell phenotype distribution is altered in AAV patients, in line with previously published work. However, no differences were found between AAV patients and TC, stressing the importance of treatment impact on this kind of studies.
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| 6. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 7. |
- Ohlsson, Sophie, et al.
(författare)
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Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation
- 2019
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:6, s. 0218272-0218272
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Tidskriftsartikel (refereegranskat)abstract
- Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), are autoimmune conditions associated with small vessel inflammation. Earlier studies indicate that complement activation via the alternative pathway plays a major role in the pathogenesis. In this study we have investigated if ANCA-activation of neutrophils from AAV patients leads to activation of the alternative complement pathway. C5a-primed neutrophils (PMN) from 10 AAV patients and 10 healthy controls (HC) were stimulated with PMA or IgG purified from PR3-ANCA positive patients (ANCA IgG). The supernatants were analyzed for release of complement proteins and markers of different granules by ELISA, and release of microparticles (MP) by flow cytometry. The ability of the supernatants to activate the alternative complement pathway was determined by incubation with normal serum and C3bBbP and C5a were measured by ELISA. MP were analyzed by flow cytometry and removed by centrifugation. The supernatants from the AAV patients' neutrophils produced significantly more C3bBbP compared with HCs (p = 0.0001). C3bBbP levels correlated with the number of MP. After removal of MP from the supernatants, alternative pathway activation was significantly lower. This study shows that primed and ANCA-stimulated neutrophils from AAV patients have a greater ability to activate the alternative complement pathway compared to primed neutrophils from healthy controls. This finding emphasizes the role of complement in the pathogenesis of AAV - underlining the therapeutic potential of C5a and other complement blockade.
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| 8. |
- Ohlsson, Susanne, et al.
(författare)
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Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies
- 2014
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Ingår i: Clinical and Experimental Immunology. - : Wiley-Blackwell. - 0009-9104 .- 1365-2249. ; 176:3, s. 363-372
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Tidskriftsartikel (refereegranskat)abstract
- Anti-neutrophil cytoplasmic antibodies (ANCA) are thought to be pathogenic in ANCA-associated vasculitis (AAV) by stimulating polymorphonuclear leucocytes (PMNs) to degranulate and produce reactive oxygen species (ROS). The aim of this study was to investigate if PMNs from AAV patients are stimulated more readily by ANCA compared with PMNs from healthy controls (HCs). Differences in ANCA characteristics that can account for different stimulation potential were also studied. PMNs from five AAV patients and five HCs were stimulated with 10 different immunoglobulins (Ig)Gs, purified from PR3-ANCA-positive patients, and ROS production, degranulation and neutrophil extracellular trap (NET) formation was measured. ANCA levels, affinity and clinical data of the AAV donors were recorded. The results show that PMNs from AAV patients produce more intracellular ROS (P=0 center dot 019), but degranulate to a similar extent as PMNs from HCs. ROS production correlated with NET formation. Factors that may influence the ability of ANCA to activate PMNs include affinity and specificity for N-terminal epitopes. In conclusion, our results indicate that PMNs from AAV patients in remission behave quite similarly to HC PMNs, with the exception of a greater intracellular ROS production. This could contribute to more extensive NET formation and thus an increased exposure of the ANCA autoantigens to the immune system.
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| 9. |
- Ohlsson, Susanne, et al.
(författare)
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Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis
- 2012
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Ingår i: Clinical and Experimental Immunology. - : Wiley-Blackwell. - 0009-9104 .- 1365-2249. ; 170:1, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is not known why ANCA develop, but it has been shown that they participate in pathogenesis by activating polymorphonuclear neutrophils (PMNs). In this study we hypothesize that dysregulation of phagocytosis in AAV leads to the accumulation of apoptotic neutrophils seen in association with blood vessels in AAV. These cells progress into secondary necrosis, contributing to tissue damage and autoantibody formation. Peripheral blood cells were counted, and phagocytosis was investigated using monocyte-derived macrophages (M circle divide) and PMNs from healthy blood donors (HBD), AAV patients and systemic lupus erythematosus (SLE) patients. Furthermore, the effect of serum was assessed. Phagocytosis was measured using flow cytometry. The results showed no deviation in monocyte subpopulations for AAV patients compared to HBDs, although there was a decrease in lymphocyte and pDC (plasmacytoid dendritic cell) populations (4.2 X 106 cells/l versus 10.4 X 106 cells/l, P andlt; 0.001). The number of neutrophils was increased (6.0 X 109 cells/l versus 3.8 X 109 cells/l, P andlt; 0.001). There were no differences found in the ability of M circle divide s to engulf apoptotic cells, nor when comparing apoptotic PMNs to become engulfed. However, serum from AAV donors tended to decrease the phagocytosis ability of M circle divide s (36%) compared to serum from HBDs (43%). In conclusion, there is no intrinsic dysfunction in the M circle divide s or in the PMNs that have an effect on phagocytic activity, but ANCA may play a role by decreasing phagocytic ability.
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| 10. |
- Ohlsson, Susanne, et al.
(författare)
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Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization.
- 2014
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Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616. ; 152:1-2, s. 10-19
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Tidskriftsartikel (refereegranskat)abstract
- Anti-neutrophil cytoplasmic antibody associated vasculitides (AAV) are conditions defined by an autoimmune small vessel inflammation. Dying neutrophils are found around the inflamed vessels and the balance between infiltrating neutrophils and macrophages is important to prevent autoimmunity. Here we investigate how sera from AAV patients may regulate macrophage polarization and function. Macrophages from healthy individuals were differentiated into M0, M1, M2a, M2b or M2c macrophages using a standardized protocol, and phenotyped according to their expression surface markers and cytokine production. These phenotypes were compared with those of macrophages stimulated with serum from AAV patients or healthy controls. While the healthy control sera induced a M0 macrophage, AAV serum promoted polarization towards the M2c subtype. No sera induced M1, M2a or M2b macrophages. The M2c subtype showed increased phagocytosis capacity compared with the other subtypes. The M2c polarization found in AAV is consistent with previous reports of increased levels of M2c-associated cytokines.
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| 11. |
- Smargianaki, Sofia, et al.
(författare)
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Disease Activity and Tendency to Relapse in ANCA-Associated Vasculitis Are Reflected in Neutrophil and Intermediate Monocyte Frequencies
- 2024
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Ingår i: Journal of Immunology Research. - 2314-7156. ; 2024
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Tidskriftsartikel (refereegranskat)abstract
- Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases with inflammation affecting small blood vessels and includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). In this study, we investigated granulocyte and monocyte subsets in a large cohort of AAV patients with emphasis on disease activity and tendency to relapse. A cohort of 105 patients with GPA or MPA and 126 healthy controls (HCs) were included. Clinical and laboratory data were collected for all patients, including disease activity, tendency to relapse, and pharmacological treatment. Using flow cytometry, circulating eosinophils, basophils, neutrophils, and monocytes were assessed. The monocytes were subdivided into classical (CD14 ++CD16 -), intermediate (CD14 ++CD16 +), and nonclassical (CD14 -CD16 +) monocytes. Mature (CD16 high) or newly released (CD16 dim) neutrophils were defined, as well as the frequency of CD177 + neutrophils. AAV patients displayed increased frequencies of intermediate monocytes, mature and newly released neutrophils, and an expanded population of CD177 + neutrophils compared to HC. MPA patients differed from GPA patients in terms of lower frequency of classical monocytes. No differences in cell frequencies regarding ANCA phenotype were observed. Paired data from 23 patients demonstrated that active disease was associated with an increased frequency of mature neutrophils and a decreased frequency of monocytes, in particular intermediate monocytes. Moreover, GPA patients with a tendency to relapse displayed an increased frequency of mature neutrophils with increased expression of CD177 +. Relapsing MPA patients, on the other hand, showed decreased frequency of intermediate monocytes. Finally, rituximab treatment was associated with increased frequencies of classical and intermediate monocytes. In conclusion, AAV patients exhibit a skewing of different neutrophil and monocyte subpopulations that are associated with disease subtypes, disease activity, rituximab treatment, and propensity to relapse. These changes may contribute to the inflammatory process and could potentially be used as biomarkers for relapse prediction.
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| 12. |
- Wang, Chao, et al.
(författare)
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A novel canine reference genome resolves genomic architecture and uncovers transcript complexity
- 2021
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- We present GSD_1.0, a high-quality domestic dog reference genome with chromosome length scaffolds and contiguity increased 55-fold over CanFam3.1. Annotation with generated and existing long and short read RNA-seq, miRNA-seq and ATAC-seq, revealed that 32.1% of lifted over CanFam3.1 gaps harboured previously hidden functional elements, including promoters, genes and miRNAs in GSD_1.0. A catalogue of canine "dark" regions was made to facilitate mapping rescue. Alignment in these regions is difficult, but we demonstrate that they harbour trait-associated variation. Key genomic regions were completed, including the Dog Leucocyte Antigen (DLA), T Cell Receptor (TCR) and 366 COSMIC cancer genes. 10x linked-read sequencing of 27 dogs (19 breeds) uncovered 22.1 million SNPs, indels and larger structural variants. Subsequent intersection with protein coding genes showed that 1.4% of these could directly influence gene products, and so provide a source of normal or aberrant phenotypic modifications. Here, the authors report an improved de novo reference genome for the domestic dog based on a female German Shepherd named Mischka. The new genome increases contiguity 55-fold over the previous dog assembly and uncovers functional elements that were not previously identifiable.
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| 13. |
- Axelsson, Erik, et al.
(författare)
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The genetic consequences of dog breed formation-Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels
- 2021
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:9
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Tidskriftsartikel (refereegranskat)abstract
- Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a similar to 10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs-the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heartderived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity.
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| 14. |
- Ball, Elisabeth, et al.
(författare)
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Repeatability of radiographic assessments for feline hip dysplasia suggest consensus scores in radiology are more uncertain than commonly assumed
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Variation in the diagnostic interpretation of radiographs is a well-recognised problem in human and veterinary medicine. One common solution is to create a 'consensus' score based on a majority or unanimous decision from multiple observers. While consensus approaches are generally assumed to improve diagnostic repeatability, the extent to which consensus scores are themselves repeatable has rarely been examined. Here we use repeated assessments by three radiologists of 196 hip radiographs from 98 cats within a health-screening programme to examine intra-observer, interobserver, majority-consensus and unanimous-consensus repeatability scores for feline hip dysplasia. In line with other studies, intra-observer and inter-observer repeatability was moderate (63-71%), and related to the reference assessment and time taken to reach a decision. Consensus scores did show reduced variation between assessments compared to individuals, but consensus repeatability was far from perfect. Only 75% of majority consensus scores were in agreement between assessments, and based on Bayesian multinomial modelling we estimate that unanimous consensus scores can have repeatabilities as low as 83%. These results clearly show that consensus scores in radiology can have large uncertainties, and that future studies in both human and veterinary medicine need to include consensus-uncertainty estimates if we are to properly interpret radiological diagnoses and the extent to which consensus scores improve diagnostic accuracy.
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| 15. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 16. |
- Bärnarp, Tora, et al.
(författare)
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Skönhet hållbarhet funktion
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna publikation redovisar studenternas enskilda arbeten. Materialet har tillkommit inom ramen för läsårets tema ”Skönhet, hållbarhet och funktion”, men varje studie utgår ifrån studenternas egna val av ämne.
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| 17. |
- Carlzon, Daniel, et al.
(författare)
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Both Low and High Serum Insulin-like Growth Factor-I Levels Associate with Increased Risk of Cardiovascular Events in Elderly Men.
- 2014
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 99:11
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Most previous prospective studies suggest that low serum insulin-like growth factor-I (IGF-I) associates with increased risk of cardiovascular disease (CVD) events while other studies suggest that high serum IGF-I associates with increased risk of CVD events. We tested the hypothesis that not only low, but also high, serum IGF-I associate with increased risk of CVD events in elderly men. Methods and Results: Serum IGF-I levels were measured in 2901 elderly men (aged 69 to 81 years) included in the prospective population-based MrOS-Sweden cohort. Data for CVD events were obtained from national Swedish registers with no loss of follow-up. During follow-up (median 5.1 yrs) 589 of the participants experienced a CVD event. The association between serum IGF-I and risk of CVD events was nonlinear, and restricted cubic spline Cox regression analysis revealed a U-shaped association between serum IGF-I levels and CVD events (p<0.01 for nonlinearity). Low as well as high serum IGF-I (quintile 1 or 5 vs. quintiles 2-4) significantly associated with increased risk for CVD events (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.02-1.54; and HR = 1.35, 95% CI 1.10-1.66, respectively). These associations remained after adjustment for prevalent CVD and multiple risk factors. High serum IGF-I associated with increased risk of coronary heart disease (CHD) events but not with risk of cerebrovascular events. Conclusion: Both low and high serum IGF-I levels are risk markers for CVD events in elderly men. The association between high serum IGF-I and CVD events is mainly driven by CHD events.
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| 18. |
- Claesson, Åsa, et al.
(författare)
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lntegrated Optical Fiber Sensors in Additive Manufactured Metal Components for Smart Manufacturing Applications
- 2019
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Ingår i: Smart Systems Integration; 13th International Conference and Exhibition on Integration Issues of Miniaturized Systems.
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Konferensbidrag (refereegranskat)abstract
- This work combines fiber optic sensors with additive manufacturing to enable integration of temperature and strain sensors in metal components. In this paper, we present a fiber optic sensor network integrated in press hardening tools to monitor the contact between the tool and the metal sheet during forming operation. The tools are manufactured through metal powder bed fusion using laser melting processes (PBF-SLM), after which the tools are prepared for sensor integration. A demonstrator press hardening tool with integrated fiber optic sensors was heated using an electric heat foil and the sensor measurements was compared to a thermal simulation model. The sensor technology is based on Fiber Bragg Gratings (FBGs), integrated at several positions along the optical fiber. FBGs are in-fiber sensors that are multiplexed. lt is possible to place hundreds of FBG sensors along one single fiber, thus allowing for quasidistributed sensing of temperature or strain. The optical fiber itself can be less than 100 micrometer in diameter, allowing for sensing at several points in a minimally invasive way, when integrated in a tool or component.
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| 19. |
- Dahlqvist, Johanna, 1979-, et al.
(författare)
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Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
- 2022
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Ingår i: Rheumatology. - Oxford, United Kingdom : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:8, s. 3461-3470
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Tidskriftsartikel (refereegranskat)abstract
- Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA(+) AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10(-61), odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10(-44), OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10(-10), OR 2.9). MPO-ANCA(+) AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10(-25), OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10(-7), OR 3.0), the latter a novel susceptibility locus for MPO-ANCA(+) granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA(+) AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
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| 20. |
- Ekman, Diana, et al.
(författare)
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Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis
- 2023
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 62:9, s. 3213-3218
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. Methods: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. Results: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. Conclusions: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.
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| 21. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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The Bone Sparing Effects of 2-Methoxyestradiol Are Mediated via Estrogen Receptor-α in Male Mice.
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:11, s. 4200-4205
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Tidskriftsartikel (refereegranskat)abstract
- 2-Methoxyestradiol (2ME2), a metabolite of 17β-estradiol (E2), exerts bone sparing effects in animal models. We hypothesized that the underlying mechanism is back conversion of 2ME2 to E2, which subsequently acts via estrogen receptor (ER)α. We measured serum E2 levels in orchidectomized wild-type (WT) mice treated with 2ME2 66.6 μg/d or placebo. In placebo-treated animals, E2 was below the detection limit. In 2ME2-treated mice, the serum E2 level was 4.97 ± 0.68 pg/mL. This corresponds to the level found in diesterus in cycling female mice. Next, we investigated bone parameters in orchidectomized WT and ERα knockout mice treated with 2ME2 or placebo for 35 days. 2ME2 (6.66 μg/d) preserved trabecular and cortical bone in WT mice. Trabecular volumetric-bone mineral density was 64 ± 20%, and trabecular bone volume/total volume was 60 ± 20% higher in the metaphyseal region of the femur in the 2ME2 group, compared with placebo (P < .01). Both trabecular number and trabecular thickness were increased (P < .01). Cortical bone mineral content in the diaphyseal region of the femur was 31 ± 3% higher in the 2ME2 group, compared with placebo (P < .001). This was due to larger cortical area (P < .001). Three-point bending showed an increased bone strength in WT 2ME2-treated animals compared with placebo (maximum load [Fmax] +19±5% in the 2ME2 group, P < .05). Importantly, no bone parameter was affected by 2ME2 treatment in ERα knockout mice. In conclusion, 2ME2 treatment of orchidectomized mice results in increased serum E2. ERα mediates the bone sparing effects of 2ME2. The likely mediator of this effect is E2 resulting from back conversion of 2ME2.
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| 24. |
- Fagman, Johan Bourghardt, 1980, et al.
(författare)
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Androgen receptor-dependent and independent atheroprotection by testosterone in male mice.
- 2010
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 151:11, s. 5428-37
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Tidskriftsartikel (refereegranskat)abstract
- The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P < 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P < 0.001) and ARKO mice (by 24%, P < 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P < 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P < 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.
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| 25. |
- Fagman, Johan Bourghardt, 1980, et al.
(författare)
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The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
- 2015
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860 .- 0892-6638. ; 29:4, s. 1540-1550
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Tidskriftsartikel (refereegranskat)abstract
- Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.-Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J. -O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
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