Age-Associated Hyper-Methylated Regions in the Human Brain Overlap with Bivalent Chromatin Domains

PMCID: PMC3454416This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Protein-Protein Interaction Analysis Highlights Additional Loci of Interest for Multiple Sclerosis

PMCID: PMC3475710This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Fatigue, sleepiness and depression in multiple sclerosis: defining the overlaps for a better phenotyping.

BACKGROUND AND OBJECTIVES To define the boundaries and the overlaps between fatigue, sleepiness and depression in patients with multiple sclerosis (MS) by using different tools for each dimension, including instrumental sleep analysis. METHODS In this cross-sectional, observational study, 71 MS patients (males/females: 20/51; mean age: 48.9 ± 10.5 years) filled in clinical questionnaires and performed polysomnography followed by maintenance of wakefulness test (MWT). Frequency and reciprocal overlap of sleepiness, fatigue and depression in MS were expressed by Eulero-Venn diagrams; standard multiple regression was used to assess the ability of symptoms to predict each other. RESULTS There was a high percentage of fatigued (70%), somnolent (45%) and depressed (27%) patients. Fatigue had the strongest overlap and correlated with both depression (beta: 0.52, p < 0.001) and sleepiness (beta: 0.74, p < 0.001). Somnolence and depression were nearly always accompanied by fatigue and were well differentiated from each other by MWT. Four MS subgroups were identified that had: (1) fatigue only; (2) fatigue and sleepiness (3) fatigue and depression; (4) fatigue, sleepiness and depression. DISCUSSION The subjective and objective tools are not able to clearly distinguish fatigue from sleepiness and depression, while only a test of vigilance can be helpful in separating somnolence and depression from each other

Protein-protein interaction analysis highlights additional <i>loci</i> of interest for Multiple Sclerosis

Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p&lt;0.0002) and significant plus suggestive (p&lt;0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p&lt;0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS

Heterogeneity in Multiple Sclerosis: Scratching the Surface of a Complex Disease

Multiple Sclerosis (MS) is the most common demyelinating disease of the central nervous system. Although the etiology and the pathogenesis of MS has been extensively investigated, no single pathway, reliable biomarker, diagnostic test, or specific treatment have yet been identified for all MS patients. One of the reasons behind this failure is likely to be the wide heterogeneity observed within the MS population. The clinical course of MS is highly variable and includes several subcategories and variants. Moreover, apart from the well-established association with the HLA-class II DRB1*15:01 allele, other genetic variants have been shown to vary significantly across different populations and individuals. Finally both pathological and immunological studies suggest that different pathways may be active in different MS patients. We conclude that these “MS subtypes” should still be considered as part of the same disease but hypothesize that spatiotemporal effects of genetic and environmental agents differentially influence MS course. These considerations are extremely relevant, as outcome prediction and personalised medicine represent the central aim of modern research

Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies

PMCID: PMC3729414The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7015/11/171. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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Multiple Sclerosis (MS) is the most common demyelinating disease of the central nervous system. Although the etiology and the pathogenesis of MS has been extensively investigated, no single pathway, reliable biomarker, diagnostic test, or specific treatment have yet been identified for all MS patients. One of the reasons behind this failure is likely to be the wide heterogeneity observed within the MS population. The clinical course of MS is highly variable and includes several subcategories and variants. Moreover, apart from the well-established association with the HLA-class II DRB1 * 15:01 allele, other genetic variants have been shown to vary significantly across different populations and individuals. Finally both pathological and immunological studies suggest that different pathways may be active in different MS patients. We conclude that these &quot;MS subtypes&quot; should still be considered as part of the same disease but hypothesize that spatiotemporal effects of genetic and environmental agents differentially influence MS course. These considerations are extremely relevant, as outcome prediction and personalised medicine represent the central aim of modern research

Seasonal Distribution of Psychiatric Births in England

There is general consensus that season of birth influences the risk of developing psychiatric conditions later in life. We aimed to investigate whether the risk of schizophrenia (SC), bipolar affective disorder (BAD) and recurrent depressive disorder (RDD) is influenced by month of birth in England to a similar extent as other countries using the largest cohort of English patients collected to date (n=57,971). When cases were compared to the general English population (n=29,183,034) all diseases showed a seasonal distribution of births (SC p=2.48E-05; BAD p=0.019; RDD p=0.015). This data has implications for future strategies of disease prevention

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

PMCID: PMC3710212This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Impact of month of birth on the development of autoimmune thyroid disease in the United Kingdom and Europe

CONTEXT: Viral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life. OBJECTIVE: Month of birth effects were investigated in three independent European Caucasian AITD datasets. DESIGN: Variation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test. SETTING: The study was conducted at a research laboratory. PATIENTS: National UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent). MAIN OUTCOME MEASURES: Case-control and family-based association studies were measured. RESULTS: No consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walter's test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort. CONCLUSION: Our results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects