| 1. |
- Kular, L, et al.
(author)
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DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
- 2018
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2397-
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Journal article (peer-reviewed)abstract
- The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
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| 2. |
- Ruhrmann, S, et al.
(author)
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Hypermethylation of MIR21 in CD4+ T cells from patients with relapsing-remitting multiple sclerosis associates with lower miRNA-21 levels and concomitant up-regulation of its target genes
- 2018
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 24:10, s. 1288-1300
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Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic and environmental risk factors. Objective: We sought to identify DNA methylation changes in CD4+ T cells in patients with relapsing-remitting (RR-MS) and secondary-progressive (SP-MS) disease and healthy controls (HC). Methods: We performed DNA methylation analysis in CD4+ T cells from RR-MS, SP-MS, and HC and associated identified changes with the nearby risk allele, smoking, age, and gene expression. Results: We observed significant methylation differences in the VMP1/MIR21 locus, with RR-MS displaying higher methylation compared to SP-MS and HC. VMP1/MIR21 methylation did not correlate with a known MS risk variant in VMP1 or smoking but displayed a significant negative correlation with age and the levels of mature miR-21 in CD4+ T cells. Accordingly, RR-MS displayed lower levels of miR-21 compared to SP-MS, which might reflect differences in age between the groups, and healthy individuals and a significant enrichment of up-regulated miR-21 target genes. Conclusion: Disease-related changes in epigenetic marking of MIR21 in RR-MS lead to differences in miR-21 expression with a consequence on miR-21 target genes.
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- Collste, K., et al.
(author)
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Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [C-11]PBR28
- 2017
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In: Molecular Psychiatry. - : NATURE PUBLISHING GROUP. - 1359-4184 .- 1476-5578. ; 22:6, s. 850-856
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Journal article (peer-reviewed)abstract
- Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [C-11]PBR28. Gray matter (GM) volume of distribution (V-T) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [C-11]PBR28 binding, and gender. There was a significant reduction of [C-11]PBR28 V-T in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM V-T and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.
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| 14. |
- Collste, K., et al.
(author)
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Test-retest reproducibility of [C-11]PBR28 binding to TSPO in healthy control subjects
- 2016
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 43:1, s. 173-183
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Journal article (peer-reviewed)abstract
- Purpose The PET radioligand [C-11]PBR28 binds to the translocator protein (TSPO), a marker of brain immune activation. We examined the reproducibility of [C-11]PBR28 binding in healthy subjects with quantification on a regional and voxel-by-voxel basis. In addition, we performed a preliminary analysis of diurnal changes in TSPO availability. Methods Twelve subjects were examined using a high-resolution research tomograph and [C-11]PBR28, six in the morning and afternoon of the same day, and six in the morning on two separate days. Regional volumes of distribution (V-T) were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. Results For the whole sample, the mean absolute variability in V (T) in the grey matter (GM) was 18.3 +/- 12.7 %. Intraclass correlation coefficients in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 min yielded a variability of 16.9 +/- 14.9 %. There was a strong correlation between the parametric and 2TCM-derived GM values (r=0.99). A significant increase in GM V-T was observed between the morning and afternoon examinations when using secondary methods of quantification (p=0.028). In the subjects examined at the same time of the day, the absolute variability was 15.9 +/- 12.2 % for the 91-min 2TCM data. Conclusion V-T of [C-11]PBR28 binding showed medium reproducibility and high reliability in GM regions. Our findings support the use of parametric approaches for determining [C-11]PBR28 V-T values, and indicate that the acquisition time could be shortened. Diurnal changes in TSPO binding in the brain may be a potential confounder in clinical studies and should be investigated further.
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| 15. |
- Isung, J, et al.
(author)
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High interleukin-6 and impulsivity : determining the role of endophenotypes in attempted suicide
- 2014
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In: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 4:e470
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Journal article (peer-reviewed)abstract
- The dysregulation of inflammation has been associated with depression and, more recently, with suicidal behaviors. The reports regarding the relationship between interleukin-6 (IL-6) and suicide attempts are inconsistent. Personality traits such as impulsivity and aggression are considered endophenotypes and important factors that underlie suicidal behaviors. The aim of the current study was to assess whether plasma and cerebrospinal fluid (CSF) levels of IL-6 are associated with personality traits among suicide attempters. We assessed the relationships among personality traits, IL-6 and violent suicide attempts. The plasma and CSF levels of IL-6 were measured in suicide attempters (plasma=58, CSF=39) using antibody-based immunoassay systems. Personality domains were assessed using the Karolinska Scale of Personality (KSP). IL-6 levels in plasma and CSF were used to predict personality domains via regression models. Plasma IL-6 was significantly and positively correlated with extraversion as well as the KSP subscales impulsivity and monotony avoidance. CSF IL-6 was positively correlated with monotony avoidance. Violent suicide attempts tended to be associated with high plasma IL-6 levels. Plasma and CSF levels of IL-6 were not significantly associated with each other. These results indicate that impulsivity and the choice of a violent suicide attempt method might be related to higher levels of IL-6 in individuals who attempt suicide. The neuroinflammation hypothesis of suicidal behavior on the basis of elevated IL-6 levels might be partly explained by the positive association between IL-6 and impulsivity, which is a key element of the suicidal phenotype.
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| 16. |
- Isung, J, et al.
(author)
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Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters
- 2012
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 2, s. e196-
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Journal article (peer-reviewed)abstract
- A dysregulated immune system influencing pathways for cytokine regulation and growth factor expression is implicated in the pathophysiology of several neuropsychiatric disorders. Here, we analyzed cerebrospinal fluid (CSF) cytokines and growth factors with an ultra-sensitive immunoassay system in 43 medication-free suicide attempters and 20 healthy male volunteers. CSF vascular endothelial growth factor (VEGF) and CSF interleukin-8 (IL-8) levels were significantly lower in suicide attempters compared with healthy controls. Further, CSF VEGF showed a significant negative correlation with depression severity. CSF IL-6 levels did not differ between suicide attempters and healthy controls. Low CSF levels of VEGF may represent a lack of trophic support to neurons and downregulation of neurogenesis in the hippocampus reflecting more severe depressive states. IL-8 has also been reported as important in neuroprotection as well as having chemokine activity in the innate immune response. The results support a role for an impaired innate immunity and dysregulation of neuroprotection in the pathophysiology of depression and suicidal behavior.
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