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Find video protocols related to scientific articles indexed in Pubmed.
HLA-DRB1*15 influences the development of brain tissue damage in early PPMS.
Neurology
PUBLISHED: 10-08-2014
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To investigate whether (1) there were differences between HLA-DRB1*15-positive and -negative patients at baseline, and (2) HLA-DRB1*15-positive patients showed a greater development of brain and spinal cord damage, as assessed by MRI, and greater progression of disability, during a 5-year follow-up, compared with HLA-DRB1*15-negative patients.
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Impact of month of birth on the development of autoimmune thyroid disease in the United Kingdom and Europe.
J. Clin. Endocrinol. Metab.
PUBLISHED: 05-19-2014
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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.
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National survey of UK medical students on the perception of neurology.
BMC Med Educ
PUBLISHED: 03-27-2014
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Medical students perceive neurology to be a difficult subject, a phenomenon described as "neurophobia". Studies investigating student attitudes towards neurology have so far been limited by small sample sizes as a consequence of being conducted within a single medical school or region. We aimed to conduct the first national survey of the perception of neurology among UK medical students.
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Regulatory genomic regions active in immune cell types explain a large proportion of the genetic risk of multiple sclerosis.
J. Hum. Genet.
PUBLISHED: 02-13-2014
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There is little understanding of how genetic variants discovered in recent genome-wide association studies are involved in the pathogenesis of multiple sclerosis (MS). We aimed to investigate which chromatin states and cell types explain genetic risk in MS. We used genotype data from 1854 MS patients and 5164 controls produced by the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium. We estimated the proportion of phenotypic variance between cases and controls explained by cell-specific chromatin state and DNase I hypersensitivity sites (DHSs) using the Genome-wide Complex Trait Analysis software. A large proportion of variance was explained by single-nucleotide polymorphisms (SNPs) in strong enhancer (SE) elements of immortalized B lymphocytes (5.39%). Three independent SNPs located within SE showed suggestive evidence of association with MS: rs12928822 (odds ratio (OR)=0.81, 95% confidence interval (CI)=0.73-0.89, P=2.48E-05), rs727263 (OR=0.75, 95% CI=0.66-0.85, P=3.26E-06) and rs4674923 (OR=0.85, 95% CI=0.79-0.92, P=1.63E-05). Genetic variants located within DHSs of CD19+ B cells explained the greatest proportion of variance. Genetic variants influencing the risk of MS are located within regulatory elements active in immune cells. This study also identifies a number of immune cell types likely to be involved in the causal cascade and that carry important implications for future studies of therapeutic design.
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Multiple sclerosis in the Iranian immigrant population of BC, Canada: prevalence and risk factors.
Mult. Scler.
PUBLISHED: 01-14-2014
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There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence.
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Prevalence of primary outcome changes in clinical trials registered on ClinicalTrials.gov: a cross-sectional study.
F1000Res
PUBLISHED: 01-01-2014
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An important principle in the good conduct of clinical trials is that a summary of the trial protocol, with a pre-defined primary outcome, should be freely available before the study commences. The clinical trials registry ClinicalTrials.gov provides one method of doing this, and once the trial is registered, any changes made to the primary outcome are documented. The objectives of this study were: to assess the proportion of registered trials on ClinicalTrials.gov that had the primary outcome changed; to assess when the primary outcome was changed in relation to the listed study start and end dates and to assess whether the primary outcome change had any relation to the study sponsor.
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Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-mediated diseases: record-linkage studies.
BMC Neurol
PUBLISHED: 11-09-2013
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Subarachnoid hemorrhage (SAH) is a devastating cause of stroke, occurring in relatively young people. It has been suggested that some immune-mediated diseases may be associated with an increased ris k of SAH.
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Similar genetics of adult and pediatric MS: Age is just a number.
Neurology
PUBLISHED: 11-06-2013
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Multiple sclerosis (MS), typically considered a disease of young adults, is increasingly recognized in early-onset pediatric cases (PMS), with an estimated 3%-5% of patients having onset before age 16 years.(1) Given its rarity, it is challenging to investigate the mechanisms that initiate MS in such young individuals and to assess whether PMS and adult MS share the same risk factors, rather than being 2 separate conditions. Population-based studies investigating the familial aggregation of MS clearly showed genes play a role in adult MS.(2) Most of this genetic risk is mediated by specific risk alleles in the major histocompatibility complex (MHC) class II region. However, genome-wide association studies (GWAS) have provided evidence for more than 50 single nucleotide polymorphisms (SNPs) of more modest effect that also influence the risk of adult MS.(3.)
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Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort.
Mult. Scler.
PUBLISHED: 11-05-2013
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Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.
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Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
FASEB J.
PUBLISHED: 10-11-2013
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The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.-Pryce, G., Visintin, C., Ramagopalan, S. V., Al-Izki, S., De Faveri, L. E., Nuamah, R. A., Mein, C. A., Montpetit, A., Hardcastle, A. J., Kooij, G., de Vries, H. E., Amor, S., Thomas, S. A., Ledent, C., Marsicano, G., Lutz, B., Thompson, A. J., Selwood, D. L., Giovannoni, G., Baker, D. Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
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DNase hypersensitive sites and association with multiple sclerosis.
Hum. Mol. Genet.
PUBLISHED: 10-02-2013
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Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.
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Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study.
Neurology
PUBLISHED: 08-14-2013
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To study whether the risk of amyotrophic lateral sclerosis (ALS) is increased in people with prior autoimmune disease.
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Lesion-to-ventricle distance and other risk factors for the persistence of newly formed black holes in relapsing-remitting multiple sclerosis.
Mult. Scler.
PUBLISHED: 07-11-2013
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Progenitor cells from the subventricular zone (SVZ) of the lateral ventricles are assumed to contribute to remyelination and resolution of black holes (BHs) in multiple sclerosis (MS). This process may depend on the distance between the lesion and the SVZ.
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The promise and challenges of blood spot methylomics.
Epigenetics
PUBLISHED: 06-19-2013
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Epigenome-wide association studies (EWAS) are being extensively performed to identify epigenetic variants associated to complex diseases. However, EWAS may identify variants that are disease-induced rather than disease-causal. Recent studies have highlighted the use of Guthrie cards to profile the methylome at birth, permitting researchers to find epigenetic variants present in patients before they are diagnosed with clinical disease, with the implicit suggestion that these variants are more likely to be disease causal. The use of Guthrie cards for research purposes throws up a number of ethical issues. We review here the promises and pitfalls of Guthrie cards for disease research.
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Integrating multiple oestrogen receptor alpha ChIP studies: overlap with disease susceptibility regions, DNase I hypersensitivity peaks and gene expression.
BMC Med Genomics
PUBLISHED: 05-31-2013
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A wealth of nuclear receptor binding data has been generated by the application of chromatin immunoprecipitation (ChIP) techniques. However, there have been relatively few attempts to apply these datasets to human complex disease or traits.
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Inactive or moderately active human promoters are enriched for inter-individual epialleles.
Genome Biol.
PUBLISHED: 05-25-2013
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Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information.
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The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis.
Mult. Scler.
PUBLISHED: 05-22-2013
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Observational studies have shown an association between lower vitamin D levels and higher risk of relapse among people with multiple sclerosis (MS). This has raised interest in potential clinical benefits of vitamin D supplementation in the management of MS. The objectives were to examine the effect of vitamin D based interventions on the relative risk of relapse in MS. Any randomised controlled trial assessing the effect on the relative risk of relapse of any formulation or dose of vitamin D, in participants with MS, was eligible. The inverse variance with random effects model in Review Manager 5.1 was used to calculate the odds ratio of relapses in high dose vitamin D treated patients vs. controls. Five studies were published as of September 2012, yielding a total of 129 high-dose vitamin D-treated patients and 125 controls. We found no significant association between high-dose vitamin D treatment and risk of MS relapse (OR 0.98, 95% CI 0.45-2.16). In conclusion, although no significant association between high-dose vitamin D treatment and risk of MS relapses was found, the studies were limited by several methodological limitations. Further larger, more prolonged studies are merited.
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Laparoscopic surgery for Crohns disease: a meta-analysis of perioperative complications and long term outcomes compared with open surgery.
BMC Surg
PUBLISHED: 05-20-2013
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Previous meta-analyses have had conflicting conclusions regarding the differences between laparoscopic and open techniques in patients with Crohns Disease. The objective of this meta-analysis was to compare outcomes in patients with Crohns disease undergoing laparoscopic or open surgical resection.
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Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies.
BMC Med
PUBLISHED: 05-13-2013
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Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases.
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TRPV1 gates tissue access and sustains pathogenicity in autoimmune encephalitis.
Mol. Med.
PUBLISHED: 05-08-2013
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Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1-/- B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.
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Vitamin D and multiple sclerosis: what is the clinical impact?
Expert Opin Med Diagn
PUBLISHED: 04-09-2013
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Evidence for a causal role for vitamin D in multiple sclerosis (MS) is being gathered. Epidemiological, molecular and animal model studies have paved the way in our understanding of the effects of vitamin D in demyelinating disease. Several clinical trials have been completed and more are under way to understand the full extent and value of vitamin D supplementation on disease progression. Many questions remain unanswered however and careful study design is increasingly pertinent. Timing of exposure, dosage and transgenerational effects are some of the several important questions that need to be addressed. In this issue, Carlson and Rose highlight these points and provide a review of vitamin D and MS with an emphasis on the most recent clinical studies. Further evidence of vitamin D deficiency as a causal factor, its molecular targets in MS and its prospect as a therapeutic and preventative agent are questions that warrant further study.
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Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies.
Epigenetics
PUBLISHED: 03-28-2013
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There is increasing evidence that interindividual epigenetic variation is an etiological factor in common human diseases. Such epigenetic variation could be genetic or non-genetic in origin, and epigenome-wide association studies (EWASs) are underway for a wide variety of diseases/phenotypes. However, performing an EWAS is associated with a range of issues not typically encountered in genome-wide association studies (GWASs), such as the tissue to be analyzed. In many EWASs, it is not possible to analyze the target tissue in large numbers of live humans, and consequently surrogate tissues are employed, most commonly blood. But there is as yet no evidence demonstrating that blood is more informative than buccal cells, the other easily accessible tissue. To assess the potential of buccal cells for use in EWASs, we performed a comprehensive analysis of a buccal cell methylome using whole-genome bisulfite sequencing. Strikingly, a buccal vs. blood comparison reveals > 6X as many hypomethylated regions in buccal. These tissue-specific differentially methylated regions (tDMRs) are strongly enriched for DNaseI hotspots. Almost 75% of these tDMRs are not captured by commonly used DNA methylome profiling platforms such as Reduced Representational Bisulfite Sequencing and the Illumina Infinium HumanMethylation450 BeadChip, and they also display distinct genomic properties. Buccal hypo-tDMRs show a statistically significant enrichment near SNPs associated to disease identified through GWASs. Finally, we find that, compared with blood, buccal hypo-tDMRs show significantly greater overlap with hypomethylated regions in other tissues. We propose that for non-blood based diseases/phenotypes, buccal will be a more informative tissue for EWASs.
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A comparative study of CSF neurofilament light and heavy chain protein in MS.
Mult. Scler.
PUBLISHED: 03-25-2013
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There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)).
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Association of vitamin D and multiple sclerosis in India.
Mult. Scler.
PUBLISHED: 03-21-2013
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Vitamin D deficiency is widely prevalent in India. The association between vitamin D status and multiple sclerosis (MS) has not been previously studied in Indians.
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Epstein-Barr virus and multiple sclerosis: association or causation?
Expert Rev Neurother
PUBLISHED: 03-02-2013
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Multiple sclerosis (MS) is a multifactorial disease in which both genetic and environmental factors and their interactions underlie causation. The current evidence base supports a strong association between Epstein-Barr virus (EBV) and MS, but potential causality remains strongly debated. It is not possible to exclude the possibility that an abnormal response to EBV infection is a consequence, rather than a cause, of the underlying pathophysiology of MS, or indeed that the association may be a reflection of a similar underlying disease mechanism. Substantial experimental progress is necessary to achieve consistency of molecular findings to complement the strong epidemiological association between EBV and MS, which cannot alone show causation. Collectively, the strength of the association between EBV and MS warrants careful development and trial of anti-EBV drugs to observe any effect on MS disease course.
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Safety and efficacy of mitoxantrone in pediatric patients with aggressive multiple sclerosis.
Eur. J. Paediatr. Neurol.
PUBLISHED: 02-22-2013
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The purpose of this study was to assess the safety and efficacy of mitoxantrone (MX) in pediatric patients with aggressive multiple sclerosis (MS).
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Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 02-21-2013
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Oligoclonal bands (OCBs) unique to the cerebrospinal fluid are used in the diagnosis of multiple sclerosis (MS). The precise prevalence of OCBs in MS and clinically isolated syndrome (CIS) is unknown. The influence of OCBs on clinical outcomes has not been quantified. OCB prevalence has been associated with latitude in a single study, if confirmed this would provide avenues for further study.
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Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis.
Mult. Scler.
PUBLISHED: 02-14-2013
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Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.
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Association of smoking with risk of multiple sclerosis: a population-based study.
J. Neurol.
PUBLISHED: 02-09-2013
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Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have shown an association between smoking and MS risk. Here, in a population-based Canadian cohort, we investigate the relationship between personal and maternal smoking exposure and the risk of MS. Using the longitudinal Canadian database, 3,157 MS cases and 756 spouse controls were administered questionnaires on active and passive smoking history. Mothers of cases and controls were also asked about their smoking exposure during pregnancy. The MS cases were more likely to have smoked than spouse controls (odds ratio 1.32, 95 % confidence interval 1.10-1.60, p = 0.003). This association was driven by an excess of ever-smokers in male MS cases. No association was seen with maternal active or passive smoking exposure during pregnancy. Ever-smoking is associated with increased MS risk in males. Further work is needed to understand the mechanism underlying this association.
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Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies.
BMC Med
PUBLISHED: 02-04-2013
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Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB).
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Next-generation sequencing in understanding complex neurological disease.
Expert Rev Neurother
PUBLISHED: 02-02-2013
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Next-generation sequencing techniques have made vast quantities of data on human genomes and transcriptomes available to researchers. Huge progress has been made towards understanding the basis of many Mendelian neurological conditions, but progress has been considerably slower in complex neurological diseases (multiple sclerosis, migraine, Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, and so on). The authors review current next-generation sequencing methodologies and present selected studies illustrating how these have been used to cast light on the genetic etiology of complex neurological diseases with specific focus on multiple sclerosis. The authors highlight particular pitfalls in next-generation sequencing experiments and speculate on both clinical and research applications of these sequencing platforms for complex neurological disorders in the future.
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Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease.
BMC Med
PUBLISHED: 01-08-2013
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Vitamin D insufficiency has been implicated in autoimmunity. ChIP-seq experiments using immune cell lines have shown that vitamin D receptor (VDR) binding sites are enriched near regions of the genome associated with autoimmune diseases. We aimed to investigate VDR binding in primary CD4+ cells from healthy volunteers.
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Rare variants in the CYP27B1 gene are associated with multiple sclerosis.
Ann. Neurol.
PUBLISHED: 12-23-2011
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Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering.
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Vitamin D deficiency--do we follow our own advice?
Clin Med
PUBLISHED: 12-21-2011
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Over the last few years, vitamin D deficiency has emerged as a risk factor for many diseases. Public awareness of the importance of the sunshine vitamin is increasing, however deficiency remains an ongoing problem. Is an awareness of the importance of vitamin D enough to promote healthy people to take supplements or is a different approach required? In this article the importance of vitamin D is discussed and data showing that knowledge of this is not sufficient to encourage people to take supplements are presented.
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Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis.
Eur. J. Hum. Genet.
PUBLISHED: 11-16-2011
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Genome-wide association studies (GWAS), although efficient to detect genes involved in complex diseases, are not designed to measure the real effect of the genes. This is illustrated here by the example of IL2RA in multiple sclerosis (MS). Association between IL2RA and MS is clearly established, although the functional variation is still unknown: the effect of IL2RA might be better described by several SNPs than by a single one. This study investigates whether a pair of SNPs better explains the observed linkage and association data than a single SNP. In total, 522 trio families and 244 affected sib-pairs were typed for 26 IL2RA SNPs. For each SNP and pairs of SNPs, the phased genotypes of patients and controls were compared to determine the SNP set offering the best risk discrimination. Consistency between the genotype risks provided by the retained set and the identical by descent allele sharing in affected sib-pairs was assessed. After controlling for multiple testing, the set of SNPs rs2256774 and rs3118470, provides the best discrimination between the case and control genotype distributions (P-corrected=0.009). The relative risk between the least and most at-risk genotypes is 3.54 with a 95% confidence interval of [2.14-5.94]. Furthermore, the linkage information provided by the allele sharing between affected sibs is consistent with the retained set (P=0.80) but rejects the SNP reported in the literature (P=0.006). Establishing a valid modeling of a disease gene is essential to test its potential interaction with other genes and to reconstruct the pathophysiological pathways.
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The effect of gender in clinically isolated syndrome (CIS): a meta-analysis.
Mult. Scler.
PUBLISHED: 10-12-2011
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A clinically isolated syndrome compatible with demyelination (CIS) is the initial presentation for the majority of people that go on to develop multiple sclerosis (MS). There has previously been little work examining the effect of gender on the development and progression of CIS.
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Vitamin D-gene interactions in multiple sclerosis.
J. Neurol. Sci.
PUBLISHED: 05-10-2011
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Vitamin D has been studied for over a century and its functions related to calcium homeostasis are well established. Over the last 30 years or so it has become increasingly clear that it has a wider role in physiology and, importantly, also in disease. Vitamin D deficiency has been linked to multiple sclerosis (MS); however the molecular mechanisms of this association were poorly understood. Recent technological advances have provided major insights as to how vitamin D may exert its role, particularly through the actions of the vitamin D receptor (VDR). In this review we aim to highlight the importance of the interaction between vitamin D and MS associated genes which provide a biological basis for the association between vitamin D and MS risk.
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Role of the HLA system in the association between multiple sclerosis and infectious mononucleosis.
Arch. Neurol.
PUBLISHED: 04-13-2011
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To determine whether multiple sclerosis (MS) and infectious mononucleosis (IM) share common HLA associations.
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Epigenetic mechanisms in multiple sclerosis and the major histocompatibility complex (MHC).
Discov Med
PUBLISHED: 03-31-2011
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Multiple sclerosis (MS) is a complex disorder of the central nervous system characterized by demyelination, axonal loss, and inflammation. The cause of MS is currently unknown although genetic and environmental factors contribute to etiology. The relative importance of each has been disputed; however, now it is clear that much of the disease results from the interaction of the environment and the genetics. Epigenetic modifications within the major histocompatibility complex (MHC) likely mediate interactions at this locus with current known environmental risk factors--vitamin D, Epstein-Barr virus, and smoking. Maternal parent-of-origin effects, month of birth effects and transgenerational differences in allele frequency are also evident in MS and may be mediated by sex-specific epigenetic mechanisms. Differences in epigenetic marks characterize monozygotic twin pairs and may explain discordance. There is promise of potential therapeutic strategies to be found in the epigenetic mechanisms at work in MS.
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Epidemiology of multiple sclerosis.
Neurol Clin
PUBLISHED: 03-29-2011
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Multiple sclerosis (MS) is the most common disease of the central nervous system that causes permanent disability in young adults. Based on strong circumstantial evidence, MS is considered to be putative autoimmune disorder, but much remains to be understood about the etiology and clinical onset of the disease. It seems unlikely that MS results from a single causative event, but rather is the result of genetic and environmental factors and the interactions thereof. This article discusses the epidemiology of MS.
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Of mice and men: experimental autoimmune encephalitis and multiple sclerosis.
Eur. J. Clin. Invest.
PUBLISHED: 03-21-2011
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Research using experimental autoimmune encephalitis (EAE) models accounts for almost 20% of the papers. published in multiple sclerosis (MS).
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Season of birth and anorexia nervosa.
Br J Psychiatry
PUBLISHED: 03-17-2011
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Our aim was to investigate whether there is a season-of-birth effect in anorexia nervosa. In a meta-analysis, we compared the distribution of anorexia births (n = 1293) from four independent UK cohorts to that of the general UK population (n = 21 914 037), using both the Walter & Elwood seasonality and chi-squared tests. We found an excess of anorexia births from March to June (odds ratio (OR) = 1.15, 95% CI 1.03-1.29, P = 0.012) and a deficit from September to October (OR = 0.8, 95% CI 0.68-0.94, P = 0.007). These results indicate that environmental risk factor(s) are operative during gestation or immediately after birth and their identification will be important for disease prevention strategies.
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Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians.
J. Neurol. Sci.
PUBLISHED: 02-17-2011
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Multiple sclerosis (MS) is determined by interactions between genes and environment and the influence of vitamin D adequacy has been proposed. Previous studies have shown that serum 25-hydroxyvitamin D (25(OH)D) levels are genetically influenced. Polymorphisms in vitamin D pathway genes are candidates for association with MS susceptibility.
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Early life child exposure and the risk of multiple sclerosis: a population based study.
J. Neurol. Sci.
PUBLISHED: 01-25-2011
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The precise aetiology of multiple sclerosis (MS) is yet to be conclusively determined, but both genes and environment and interactions thereof are important. It has been suggested that early life child exposure influences MS susceptibility. Here, in a population-based cohort, we investigated whether infant day care attendance influences the subsequent risk to develop MS. We identified 379 MS index cases and 101 spousal controls, all of whom were a single child (i.e. they had no biological sibs, half-sibs, step-sibs, adopted sibs) from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of infant day care attendance was compared for index cases and controls and the results were not statistically significant. Exposure to other infants during early childhood thus does not appear to be a risk factor for MS.
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Smoking and multiple sclerosis: an updated meta-analysis.
PLoS ONE
PUBLISHED: 01-13-2011
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Multiple sclerosis (MS) is a leading cause of disability in young adults. Susceptibility to MS is determined by environmental exposure on the background of genetic risk factors. A previous meta-analysis suggested that smoking was an important risk factor for MS but many other studies have been published since then.
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What is Next for the Genetics of Multiple Sclerosis?
Autoimmune Dis
PUBLISHED: 01-12-2011
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We review here our current understanding of the genetic aetiology of the common complex neurological disease multiple sclerosis (MS). The strongest genetic risk factor for MS is the major histocompatibility complex which was identified in the 1970s. In 2011, after a number of genome-wide association studies have been completed and have identified approximately 20 new genes for MS, we ask the question-what is next for the genetics of MS?
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Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study.
BMC Med
PUBLISHED: 01-10-2011
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Venous thromboembolism (VTE) is a common complication during and after a hospital admission. Although it is mainly considered a complication of surgery, it often occurs in people who have not undergone surgery, with recent evidence suggesting that immune-mediated diseases may play a role in VTE risk. We, therefore, decided to study the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in people admitted to hospital with a range of immune-mediated diseases.
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Geography of hospital admissions for multiple sclerosis in England and comparison with the geography of hospital admissions for infectious mononucleosis: a descriptive study.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 01-06-2011
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It is well recognised that variation in the geographical distribution of multiple sclerosis (MS) exists. Early studies in England have shown the disease to have been more common in the North than the South. However, this could be an artefact of inaccurate diagnosis and ascertainment, and recent data on MS prevalence are lacking. In the present study, data were analysed to provide a more contemporary map of the distribution of MS in England and, as infectious mononucleosis (IM) has been shown to be associated with the risk of MS, the geographical distribution of IM with that of MS was compared.
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The epidemiology of multiple sclerosis in Scotland: inferences from hospital admissions.
PLoS ONE
PUBLISHED: 01-02-2011
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Multiple sclerosis (MS) is a neurological disorder with a highly characteristic disease distribution. Prevalence and incidence in general increase with increasing distance from the equator. Similarly the female to male sex ratio increases with increasing latitude. Multiple possible risk factors have been hypothesised for this epidemiological trend, including human leukocyte antigen allele frequencies, ultraviolet exposure and subsequent vitamin D levels, smoking and Epstein-Barr virus. In this study we undertook a study of medical records across Scotland on an NHS health board level of resolution to examine the epidemiology of MS in this region.
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Seasonality of admissions with multiple sclerosis in Scotland.
Eur. J. Neurol.
PUBLISHED: 12-29-2010
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? Previous studies have described a seasonal pattern of MS relapse risk. Vitamin D and infectious triggers are two major candidate environmental risk factors proposed to account for this effect. We aimed to assess MS admissions in Scotland for a possible effect of seasonality.
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Contribution of genetic, epigenetic and transcriptomic differences to twin discordance in multiple sclerosis.
Expert Rev Neurother
PUBLISHED: 09-08-2010
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Evaluation of: Baranzini SE, Mudge J, van Velkinburgh JC et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464, 1351-1356 (2010). Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS. Genetically identical (monozygotic) twins have a concordance rate for MS of approximately 30%, lending support to the notion that the disease has a complex etiology, developing as a result of genetic and environmental factors and their interactions. However, recent studies have highlighted the fact that monozygotic twins might not actually be genetically identical. In an effort to see if this can explain MS twin discordance, Baranzini and colleagues sequenced the genome from a pair of monozygotic twins discordant for MS, and also examined DNA methylation and gene expression across the genome in this twin pair and an additional two more twin pairs. No consistent differences in DNA sequence, DNA methylation or gene expression were found. Here we put these findings into context and discuss their significance.
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A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.
Genome Res.
PUBLISHED: 08-24-2010
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Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohns disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases.
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Congenital abnormalities and multiple sclerosis.
BMC Neurol
PUBLISHED: 08-07-2010
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There is a strong maternal parent-of-origin effect in determining susceptibility to multiple sclerosis (MS). One hypothesis is that an abnormal intrauterine milieu leading to impaired fetal development could plausibly also result in increased susceptibility to MS. A possible marker for this intrauterine insult is the presence of a non-fatal congenital anomaly.
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The emerging role of vitamin D binding protein in multiple sclerosis.
J. Neurol.
PUBLISHED: 08-05-2010
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Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). A growing body of evidence supports a role for vitamin D in MS aetiology. Vitamin D binding protein (DBP) is the major plasma carrier of vitamin D metabolites and genetic differences in DBP gene have been found to influence vitamin D levels. We review here evidence supporting a role of DBP in MS. Several recent studies show that DBP levels in the cerebrospinal fluid correlate with MS course, being lower during relapses and higher in the secondary progressive phase. Further studies are needed to elucidate the potential use of DBP as a biological marker of MS course, but may be of use given the current lack of diagnostic tools for the prediction of MS development and progression.
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Parent-of-origin effects at the major histocompatibility complex in multiple sclerosis.
Hum. Mol. Genet.
PUBLISHED: 07-15-2010
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Multiple sclerosis (MS) susceptibility is characterized by maternal parent-of-origin effects and increased female penetrance. In 7796 individuals from 1797 MS families (affected individuals n = 2954), we further implicate epigenetic modifications within major histocompatibility complex (MHC) class II haplotypes as mediating these phenomena. Affected individuals with the main MS-associated allele HLA-DRB1*15 had a higher female-to-male ratio versus those lacking it (P = 0.00023). Distorted transmission of MHC haplotypes by both parent-of-origin and gender-of-affected-offspring was most evident in the maternal HLA-DRB1*15 transmission to affected female offspring (OR = 3.31, 95% CI = 2.59-4.24) contrasting with similarity among maternal transmission to affected male offspring (OR = 2.13, 95% CI = 1.44-3.14), paternal transmissions to affected female (OR = 2.14, 95% CI = 1.64-2.78) and male (OR = 2.16, 95% CI = 1.37-3.39) offspring. Significant parent-of-origin effects were observed in affected females (maternal: P = 9.33 x 10(-42); paternal: P = 1.12 x 10(-15); comparison: P = 0.0014), but not in affected males (maternal: P = 6.70 x 10(-8); paternal: P = 2.54 x 10(-6); comparison: P = 0.95). Conditional logistic regression analysis revealed further differential risk of HLA diplotypes. Risks for HLA-DRB1*15 and likely for other HLA-DRB1 haplotypes were restricted by (i) parent-of-origin, (ii) gender-of-offspring and (iii) trans epistasis in offspring. These findings may illuminate the gender bias characterizing autoimmunity overall. They raise questions about the concept of restricted antigen presentation in autoimmunity and suggest that gender-specific epigenetic interactions may be the driving forces behind the MHC haplotypic associations. Haplotype-specific epigenetic modifications at MHC class II and their decay appear to be at the heart of MS pathogenesis and inheritance of risk, providing the focus for gene-environment interactions that determine susceptibility and resistance.
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A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.
Nat. Med.
PUBLISHED: 07-09-2010
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Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.
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Multiple sclerosis: risk factors, prodromes, and potential causal pathways.
Lancet Neurol
PUBLISHED: 07-09-2010
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Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.
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Multiple sclerosis, vitamin D, and HLA-DRB1*15.
Neurology
PUBLISHED: 06-10-2010
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Multiple sclerosis (MS) has a remarkable geographic distribution inversely paralleling that of regional ultraviolet radiation, supporting the hypothesis that vitamin D plays a central role in the disease etiology. The major histocompatibility complex exerts the largest genetic contribution to MS susceptibility, but much risk remains unexplained and direct gene-environment interaction is a strong candidate for this additional risk. Such interactions may hold the key for disease prevention.
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An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis.
PLoS ONE
PUBLISHED: 05-19-2010
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Multiple sclerosis (MS) appears to develop in genetically susceptible individuals as a result of environmental exposures. Epstein-Barr virus (EBV) infection is an almost universal finding among individuals with MS. Symptomatic EBV infection as manifested by infectious mononucleosis (IM) has been shown in a previous meta-analysis to be associated with the risk of MS, however a number of much larger studies have since been published.
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The effect of single nucleotide polymorphisms from genome wide association studies in multiple sclerosis on gene expression.
PLoS ONE
PUBLISHED: 03-14-2010
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Multiple sclerosis (MS) is a complex neurological disorder. Its aetiology involves both environmental and genetic factors. Recent genome-wide association studies have identified a number of single nucleotide polymorphisms (SNPs) associated with susceptibility to (MS). We investigated whether these genetic variations were associated with alteration in gene expression.
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IGHV4-39 deletion polymorphism does not associate with risk or outcome of multiple sclerosis.
J. Neuroimmunol.
PUBLISHED: 03-05-2010
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The restricted use of immunoglobulin heavy chain variable (IGHV) family 4 gene segments by clonally expanded B cells in brain lesions and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is well documented. Specifically, the overrepresentation of gene IGHV4-39 has been highlighted in multiple studies. To investigate the role of IGHV4-39 in MS, we screened 193 MS cases, representing the extremes of clinical outcome (benign and malignant), and 187 controls for a previously reported germline deletion polymorphism containing IGHV4-39. We did not reveal a genetic association linking this polymorphism to MS risk or progression.
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Is Lamarckian evolution relevant to medicine?
BMC Med. Genet.
PUBLISHED: 02-24-2010
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200 years have now passed since Darwin was born and scientists around the world are celebrating this important anniversary of the birth of an evolutionary visionary. However, the theories of his colleague Lamarck are treated with considerably less acclaim. These theories centre on the tendency for complexity to increase in organisms over time and the direct transmission of phenotypic traits from parents to offspring.
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Environmental factors and their timing in adult-onset multiple sclerosis.
Nat Rev Neurol
PUBLISHED: 02-16-2010
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Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease.
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Childhood cows milk allergy and the risk of multiple sclerosis: a population based study.
J. Neurol. Sci.
PUBLISHED: 01-21-2010
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Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis (MS) and vitamin D is hypothesised to contribute to disease susceptibility. Cows milk allergy (CMA) is a common childhood allergy arising from an immune system imbalance and can also lead to vitamin D deficiency due to dairy food avoidance. Here, we investigated whether or not CMA influences the subsequent risk to develop MS in a population-based cohort. We identified 6638 MS index cases and 2509 spousal controls with CMA information from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of CMA was compared between index cases and controls. No significant differences were found. Childhood CMA thus does not appear to be a risk factor for MS.
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No evidence for an effect of DNA methylation on multiple sclerosis severity at HLA-DRB1*15 or HLA-DRB5.
J. Neuroimmunol.
PUBLISHED: 01-16-2010
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Multiple sclerosis (MS) is a complex neurological disease with huge variability in disease outcome. The majority of MS genetic susceptibility is determined by major histocompatibility complex (MHC) alleles, in particular haplotypes carrying HLA-DRB1*1501. HLA-DRB1*1501 also affects the clinical outcome of the disease and animal research has suggested that HLA-DRB5 interacts with HLA-DRB1*1501 to influence disease severity. We used an extremes-of-outcome design with 48 benign and 20 malignant MS patients to assess whether or not DNA methylation at HLA-DRB1*1501 and/or HLA-DRB5 also contributes to MS phenotypic heterogeneity. We found no significant effect of DNA methylation across HLA-DRB1*1501 and HLA-DRB5 on severity, although we cannot rule out time- or tissue-specific effects of DNA methylation.
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Clinical prognostic factors in multiple sclerosis: a natural history review.
Nat Rev Neurol
PUBLISHED: 12-03-2009
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This Review summarizes the natural history studies on multiple sclerosis (MS) that have evaluated prognostic factors. Reassessment of prognostic factors is warranted, as our ability to offer patients a reliable prognosis is limited, yet we rely on this knowledge to appropriately design clinical trials and interpret their results. The selection criteria for studies to review included a geographical referral base, duration of at least 9 years, prospective design, and populations of at least 100 patients with MS. For all forms of MS combined, negative prognostic factors included progressive disease, and disability at 2 and 5 years. In relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) combined, negative prognostic factors were the onset of progression, a higher relapse rate, greater disability in the first 5 years, a shorter interval to the second relapse, and the involvement of more systems. Additional negative factors include a shorter time to progression in SPMS and a faster rate of disability in the first 2 and 5 years in primary progressive MS (PPMS). Onset of progression, relapse rate and disability in the initial 5 years could be fruitful therapeutic targets; however, longer-term clinical trials will be required to justify these end points.
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Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis.
Eur. J. Hum. Genet.
PUBLISHED: 11-25-2009
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A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case-Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values < or =0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648-0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716-0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS.
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Multiple sclerosis: major histocompatibility complexity and antigen presentation.
Genome Med
PUBLISHED: 11-06-2009
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Multiple sclerosis (MS), like many putative autoimmune diseases, has been known to be associated with the human leukocyte antigen (HLA) class II region for more than 3 decades. However, exactly how HLA class II alleles increase the risk of MS is not yet conclusively known. Recent work in large human cohorts has highlighted the fact that nearly all common HLA-DRB1 allelotypes are either positively or negatively associated with the disease, detracting from allele-specific antigen presentation as the sole mechanism of MHC associated disease susceptibility. Here, we put into context recent data on the HLA class II region in MS, including allelic heterogeneity, gene-environment interactions and epigenetics. It is clear that a complete understanding of the epistatic interactions and epigenetic features of this region will be crucial to comprehending disease pathogenesis.
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Type 1 diabetes mellitus and multiple sclerosis: common etiological features.
Nat Rev Endocrinol
PUBLISHED: 11-03-2009
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Type 1 diabetes mellitus and multiple sclerosis have been largely seen as different, organ-specific diseases, which are managed by different medical specialties. Research studies on these diseases have for the most part followed independent tracks. In this Review, we highlight the latest epidemiological and genetic findings, which have identified many features common to both disorders. Experts consider it increasingly likely that the environment contributes substantially to this overlap. However, although genetic elements that are distinct to each disease probably determine the ultimate form of autoimmunity that is manifested, strikingly broad parallels are seen between the components of genetic risk of type 1 diabetes mellitus and multiple sclerosis. Similarities and differences between these two diseases draw attention to shared disease pathways but insights into each disorder are providing mutual illumination of their pathogenesis.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.