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1.  The Refinement of Genetic Predictors of Multiple Sclerosis 
PLoS ONE  2014;9(5):e96578.
A recent genome wide association study (GWAS) demonstrated that more than 100 genetic variants influence the risk of multiple sclerosis (MS). We investigated what proportion of the general population can be considered at high genetic risk of MS, whether genetic information can be used to predict disease development and how the recently found genetic associations have influenced these estimates. We used summary statistics from GWAS in MS to estimate the distribution of risk within a large simulated general population. We profiled MS associated loci in 70 MS patients and 79 healthy controls (HC) and assessed their position within the distribution of risk in the simulated population. The predictive performance of a weighted genetic risk score (wGRS) on disease status was investigated using receiver operating characteristic statistics. When all known variants were considered, 40.8% of the general population was predicted to be at reduced risk, 49% at average, 6.9% at elevated and 3.3% at high risk of MS. Fifty percent of MS patients were at either reduced or average risk of disease. However, they showed a significantly higher wGRS than HC (median 13.47 vs 12.46, p = 4.08×10−10). The predictive performance of the model including all currently known MS associations (area under the curve = 79.7%, 95%CI = 72.4%–87.0%) was higher than that of models considering previously known associations. Despite this, considering the relatively low prevalence of MS, the positive predictive value was below 1%. The increasing number of known associated genetic variants is improving our ability to predict the development of MS. This is still unlikely to be clinically useful but a more complete understanding of the complexity underlying MS aetiology and the inclusion of environmental risk factors will aid future attempts of disease prediction.
PMCID: PMC4008598  PMID: 24794218
2.  Bradykinesia-Akinesia Incoordination Test: Validating an Online Keyboard Test of Upper Limb Function 
PLoS ONE  2014;9(4):e96260.
The Bradykinesia Akinesia Incoordination (BRAIN) test is a computer keyboard-tapping task that was developed for use in assessing the effect of symptomatic treatment on motor function in Parkinson's disease (PD). An online version has now been designed for use in a wider clinical context and the research setting.
Validation of the online BRAIN test was undertaken in 58 patients with Parkinson's disease (PD) and 93 age-matched, non-neurological controls. Kinesia scores (KS30, number of key taps in 30 seconds), akinesia times (AT30, mean dwell time on each key in milliseconds), incoordination scores (IS30, variance of travelling time between key presses) and dysmetria scores (DS30, accuracy of key presses) were compared between groups. These parameters were correlated against total motor scores and sub-scores from the Unified Parkinson's Disease Rating Scale (UPDRS).
Mean KS30, AT30 and IS30 were significantly different between PD patients and controls (p≤0.0001). Sensitivity for 85% specificity was 50% for KS30, 40% for AT30 and 29% for IS30. KS30, AT30 and IS30 correlated significantly with UPDRS total motor scores (r = −0.53, r = 0.27 and r = 0.28 respectively) and motor UPDRS sub-scores. The reliability of KS30, AT30 and DS30 was good on repeated testing.
The BRAIN test is a reliable, convenient test of upper limb motor function that can be used routinely in the outpatient clinic, at home and in clinical trials. In addition, it can be used as an objective longitudinal measurement of emerging motor dysfunction for the prediction of PD in at-risk cohorts.
PMCID: PMC4004565  PMID: 24781810
3.  Immunopathogenic Mechanisms in Tourette Syndrome: A Critical Review 
Tourette syndrome (TS) has a multifactorial etiology, in which genetic, environmental, immunological and hormonal factors interact to establish vulnerability. This review: (i) summarizes research exploring the exposure of TS patients to immune-activating environmental factors, and (ii) focuses on recent findings supporting a role of the innate and adaptive immune systems in the pathogenesis of TS and related disorders. A higher exposure prior to disease onset to group A β-haemolytic streptococcal (GABHS) infections in children with tics and obsessive-compulsive (OC) symptoms has been documented, although their influence upon the course of disease remains uncertain. Increased activation of immune responses in TS is suggested by changes in gene expression profiles of peripheral immune cells, relative frequency of lymphocyte subpopulations, and synthesis of immune effector molecules. Increased activity of cell-mediated mechanisms is suggested by the increased expression of genes controlling natural killer and cytotoxic T cells, increased plasma levels of some pro-inflammatory cytokines which correlate with disease severity, and increased synthesis of antineuronal antibodies. Important methodological differences might account for some inconsistency among results of studies addressing autoantibodies in TS. Finally, a general predisposition to autoimmune responses in TS patients is indicated by the reduced frequency of regulatory T cells, which induce tolerance towards self-antigens. Although the pathogenic role of immune activation in TS has not been definitively proven, a pathophysiological model is proposed to explain the possible effect of immunity upon dopamine transmission regulation and the generation of tics.
PMCID: PMC3972005  PMID: 19353683
group A beta haemolytic Streptococcus; tic; tourette syndrome; autoimmunity; antineuronal antibodies
4.  Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis 
Journal of Neurology  2013;261:316-323.
Patients with highly active relapsing-remitting multiple sclerosis (RRMS) are at greater risk for disease progression and may respond differently to MS therapeutics than those with less active disease. The current post hoc analysis evaluated the effects of daclizumab high-yield process (DAC HYP) vs. placebo in patients with highly active RRMS in the SELECT study. Highly active RRMS was defined as patients with ≥2 relapses in the year before randomization and ≥1 gadolinium-enhancing (Gd+) lesion at baseline. Because results were similar in the DAC HYP dose groups, data from the DAC HYP arms were pooled for analysis. Treatment with DAC HYP resulted in similar effects in highly active (n = 88) and less active (n = 506) RRMS patients. DAC HYP reduced the annualized relapse rate by 50 % and 51 % in the highly active (p = 0.0394) and less active (p < 0.0001) groups vs. placebo, respectively (interaction p = 0.82). DAC HYP reduced new/newly-enlarging T2 lesions (highly active RRMS 76 % reduction, p < 0.0001; less active RRMS 73 % reduction, p < 0.0001; interaction p = 0.18), the risk of having more Gd+ lesions (highly active RRMS 89 % reduction, p < 0.0001; less active RRMS 86 % reduction, p < 0.0001; interaction p = 0.46), and sustained disability progression (highly active RRMS 88 % reduction, p = 0.0574; less active RRMS 46 % reduction, p = 0.0383; interaction p = 0.22) vs. placebo. DAC HYP efficacy was similar across the spectrum of MS disease activity as assessed prior to treatment initiation.
PMCID: PMC3915085  PMID: 24375015
Relapsing-remitting multiple sclerosis; Drug therapy; Treatment outcome; Safety; Magnetic resonance imaging
5.  Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis 
Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.
By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.
These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.
PMCID: PMC3895761  PMID: 24364862
Multiple sclerosis; Experimental autoimmune encephalomyelitis; Neurodegeneration; Remyelination; Gliosis
6.  Neuroprotection in a Novel Mouse Model of Multiple Sclerosis 
PLoS ONE  2013;8(11):e79188.
Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine) or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment.
PMCID: PMC3817036  PMID: 24223903
7.  Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis 
PLoS ONE  2013;8(10):e76907.
Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2tm1Zim) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2Dgen) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2tm1Zim mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.
PMCID: PMC3793915  PMID: 24130809
8.  Increased Neurofilament Light Chain Blood Levels in Neurodegenerative Neurological Diseases 
PLoS ONE  2013;8(9):e75091.
Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies.
We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF.
Patients with Alzheimer’s disease (AD) (30.8 pg/ml, n=20), Guillain-Barré-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002 for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001). Similar differences were seen in corresponding CSF samples. CSF and serum levels correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70, p<0.0001), but not in CP (r=0.11, p=0.3739). The sensitivity and specificity of serum NfL for separating ALS from healthy controls was 91.3% and 91.0%.
We developed and validated a novel ECL based sandwich immunoassay for the NfL protein in serum (NfLUmea47:3); levels in ALS were more than 20-fold higher than in controls. Our data supports further longitudinal studies of serum NfL in neurodegenerative diseases as a potential biomarker of on-going disease progression, and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.
PMCID: PMC3779219  PMID: 24073237
9.  Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS – Neurofilament as a Surrogate of Disease Progression 
PLoS ONE  2013;8(8):e70019.
Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.
SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12–24 and 0–24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.
Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12–24 months p = 0.043, Nfh 0–24 months p = 0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.
The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.
PMCID: PMC3731296  PMID: 23936370
10.  Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies 
BMC Medicine  2013;11:171.
Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases.
We analyzed a database of linked statistical records of hospital admissions and death registrations for the whole of England (from 1999 to 2011). Rate ratios for immune-mediated disease were determined, comparing vitamin D deficient cohorts (individuals admitted for vitamin D deficiency or markers of vitamin D deficiency) with comparison cohorts.
After hospital admission for either vitamin D deficiency, osteomalacia or rickets, there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, thyrotoxicosis, and significantly reduced risks for asthma and myxoedema.
This study shows that patients with vitamin D deficiency may have an increased risk of developing some immune-mediated diseases, although we cannot rule out reverse causality or confounding. Further study of these associations is warranted and these data may aid further public health studies.
PMCID: PMC3729414  PMID: 23885887
Vitamin D; Immune disease; Hospital episode statistics
11.  Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease 
BMC Medicine  2013;11:163.
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.
We extracted CD4+ cells from nine healthy volunteers. Each sample underwent VDR ChIP-seq. Our results were analyzed in relation to published ChIP-seq and RNA-seq data in the Genomic HyperBrowser. We used MEMEChIP for de novo motif discovery. 25-Hydroxyvitamin D levels were measured using liquid chromatography–tandem mass spectrometry and samples were divided into vitamin D sufficient (25(OH)D ≥75 nmol/L) and insufficient/deficient (25(OH)D <75 nmol/L) groups.
We found that the amount of VDR binding is correlated with the serum level of 25-hydroxyvitamin D (r = 0.92, P= 0.0005). In vivo VDR binding sites are enriched for autoimmune disease associated loci, especially when 25-hydroxyvitamin D levels (25(OH)D) were sufficient (25(OH)D ≥75: 3.13-fold, P<0.0001; 25(OH)D <75: 2.76-fold, P<0.0001; 25(OH)D ≥75 enrichment versus 25(OH)D <75 enrichment: P= 0.0002). VDR binding was also enriched near genes associated specifically with T-regulatory and T-helper cells in the 25(OH)D ≥75 group. MEME ChIP did not identify any VDR-like motifs underlying our VDR ChIP-seq peaks.
Our results show a direct correlation between in vivo 25-hydroxyvitamin D levels and the number of VDR binding sites, although our sample size is relatively small. Our study further implicates VDR binding as important in gene-environment interactions underlying the development of autoimmunity and provides a biological rationale for 25-hydroxyvitamin D sufficiency being based at 75 nmol/L. Our results also suggest that VDR binding in response to physiological levels of vitamin D occurs predominantly in a VDR motif-independent manner.
PMCID: PMC3710212  PMID: 23849224
Vitamin D; Autoimmune disease; ChIP-seq; Functional genomics
12.  Inactive or moderately active human promoters are enriched for inter-individual epialleles 
Genome Biology  2013;14(5):R43.
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.
First, in a small sample set, we demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable over at least 2 years. Then, we show that iiDMRs are associated with changes in chromatin state as measured by inter-individual differences in histone variant H2A.Z levels. However, the correlation of promoter iiDMRs with gene expression is negligible and not improved by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for housekeeping genes, and either depleted for H3K4me3/enriched for H3K27me3 or lacking both these marks in human embryonic stem cells. The preferential enrichment of iiDMRs at regions of relative transcriptional inactivity validates in a larger independent cohort, and is reminiscent of observations previously made for promoters that undergo hypermethylation in various cancers, in vitro cell culture and ageing.
Our work identifies potential key features of epiallelic variation in humans, including temporal stability of non-genetically determined epialleles, and concomitant perturbations of chromatin state. Furthermore, our work suggests a novel mechanistic link among inter-individual epialleles observed in the context of normal variation, cancer and ageing.
PMCID: PMC4053860  PMID: 23706135
Epigenetics; DNA methylation; epialleles
13.  Correction: Meta-Analysis of the Relationship between Multiple Sclerosis and Migraine 
PLoS ONE  2013;8(4):10.1371/annotation/274e5ef1-79aa-48f7-af62-0594d5c1354e.
PMCID: PMC3613438
14.  Assessing fracture risk in people with MS: a service development study comparing three fracture risk scoring systems 
BMJ Open  2013;3(3):e002508.
Suboptimal bone health is increasingly recognised as an important cause of morbidity. Multiple sclerosis (MS) has been consistently associated with an increased risk of osteoporosis and fracture. Various fracture risk screening tools have been developed, two of which are in routine use and a further one is MS-specific. We set out to compare the results obtained by these in the MS clinic population.
This was a service development study. The 10-year risk estimates of any fracture and hip fracture generated by each of the algorithms were compared.
The MS clinic at the Royal London Hospital.
88 patients with a confirmed diagnosis of MS.
Outcome measures
Mean 10-year overall fracture risk and hip fracture risk were calculated using each of the three fracture risk calculators. The number of interventions that would be required as a result of using each of these tools was also compared.
Mean 10-year fracture risk was 4.7%, 2.3% and 7.6% using FRAX, QFracture and the MS-specific calculator, respectively (p<0.0001 for difference). The agreement between risk scoring tools was poor at all levels of fracture risk.
The agreement between these three fracture risk scoring tools is poor in the MS population. Further work is required to develop and validate an accurate fracture risk scoring system for use in MS.
Trial registration
This service development study was approved by the Clinical Effectiveness Department at Barts Health NHS Trust (project registration number 156/12).
PMCID: PMC3612805  PMID: 23482989
Osteoporosis; Fracture
15.  Estimating the proportion of variation in susceptibility to multiple sclerosis captured by common SNPs 
Scientific Reports  2012;2:770.
Multiple sclerosis (MS) is a complex disease with underlying genetic and environmental factors. Although the contribution of alleles within the major histocompatibility complex (MHC) are known to exert strong effects on MS risk, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs), as well as loci that remain undiscovered. We use a recently developed method to estimate the proportion of variance in disease liability explained by 475,806 single nucleotide polymorphisms (SNPs) genotyped in 1,854 MS cases and 5,164 controls. We reveal that ~30% of MS genetic liability is explained by SNPs in this dataset, the majority of which is accounted for by common variants. These results suggest that the unaccounted for proportion could be explained by variants that are in imperfect linkage disequilibrium with common GWAS SNPs, highlighting the potential importance of rare variants in the susceptibility to MS.
PMCID: PMC3480808  PMID: 23105968
16.  Protein-Protein Interaction Analysis Highlights Additional Loci of Interest for Multiple Sclerosis 
PLoS ONE  2012;7(10):e46730.
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<0.0002) and significant plus suggestive (p<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<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.
PMCID: PMC3475710  PMID: 23094030
17.  Age-Associated Hyper-Methylated Regions in the Human Brain Overlap with Bivalent Chromatin Domains 
PLoS ONE  2012;7(9):e43840.
Recent associations between age-related differentially methylated sites and bivalently marked chromatin domains have implicated a role for these genomic regions in aging and age-related diseases. However, the overlap between such epigenetic modifications has so far only been identified with respect to age-associated hyper-methylated sites in blood. In this study, we observed that age-associated differentially methylated sites characterized in the human brain were also highly enriched in bivalent domains. Analysis of hyper- vs. hypo-methylated sites partitioned by age (fetal, child, and adult) revealed that enrichment was significant for hyper-methylated sites identified in children and adults (child, fold difference = 2.28, P = 0.0016; adult, fold difference = 4.73, P = 4.00×10−5); this trend was markedly more pronounced in adults when only the top 100 most significantly hypo- and hyper-methylated sites were considered (adult, fold difference = 10.7, P = 2.00×10−5). Interestingly, we found that bivalently marked genes overlapped by age-associated hyper-methylation in the adult brain had strong involvement in biological functions related to developmental processes, including neuronal differentiation. Our findings provide evidence that the accumulation of methylation in bivalent gene regions with age is likely to be a common process that occurs across tissue types. Furthermore, particularly with respect to the aging brain, this accumulation might be targeted to loci with important roles in cell differentiation and development, and the closing off of these developmental pathways. Further study of these genes is warranted to assess their potential impact upon the development of age-related neurological disorders.
PMCID: PMC3454416  PMID: 23028473
18.  Meta-Analysis of the Relationship between Multiple Sclerosis and Migraine 
PLoS ONE  2012;7(9):e45295.
Studies investigating a proposed association between multiple sclerosis (MS) and migraine have produced conflicting results and a great range in the prevalence rate of migraine in MS patients. By meta-analysing all available data we aimed to establish an overall estimate of any association in order to more accurately inform clinicians and care-givers about a potential association between MS and migraine.
Pubmed and EMBASE were searched to identify suitable studies. Studies were included if they were a case-control study or cohort study in which controls were not reported to have another neurological condition, were available in English, and specified migraine as a headache sub-type. The odds ratio (OR) of migraine in MS patients vs. controls was calculated using the inverse variance with random effects model in Review Manager 5.1.
Eight studies were selected for inclusion, yielding a total of 1864 MS patients and 261563 control subjects. We found a significant association between migraine and MS (OR = 2.60, 95% CI 1.12–6.04), although there was significant heterogeneity. Sensitivity analysis showed that migraine without aura was associated with MS OR = 2.29 (95% CI 1.14–4.58), with no significant heterogeneity.
MS patients are more than twice as likely to report migraine as controls. Care providers should be alerted to ask MS patients about migraine in order to treat it and potentially improve quality of life. Future work should further investigate the temporal relationship of this association and relationship to the clinical characteristics of MS.
PMCID: PMC3443216  PMID: 23024814
19.  Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course 
International Journal of MS Care  2012;14(3):105-114.
It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.
PMCID: PMC3882992  PMID: 24453741
20.  Development of protein biomarkers in cerebrospinal fluid for secondary progressive multiple sclerosis using selected reaction monitoring mass spectrometry (SRM-MS) 
Clinical proteomics  2012;9(1):9.
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). It involves damage to the myelin sheath surrounding axons and to the axons themselves. MS most often presents with a series of relapses and remissions but then evolves over a variable period of time into a slowly progressive form of neurological dysfunction termed secondary progressive MS (SPMS). The reasons for this change in clinical presentation are unclear. The absence of a diagnostic marker means that there is a lag time of several years before the diagnosis of SPMS can be established. At the same time, understanding the mechanisms that underlie SPMS is critical to the development of rational therapies for this untreatable stage of the disease.
Using high performance liquid chromatography-coupled mass spectrometry (HPLC); we have established a highly specific and sensitive selected reaction monitoring (SRM) assay. Our multiplexed SRM assay has facilitated the simultaneous detection of surrogate peptides originating from 26 proteins present in cerebrospinal fluid (CSF). Protein levels in CSF were generally ~200-fold lower than that in human sera. A limit of detection (LOD) was determined to be as low as one femtomol. We processed and analysed CSF samples from a total of 22 patients with SPMS, 7 patients with SPMS treated with lamotrigine, 12 patients with non-inflammatory neurological disorders (NIND) and 10 healthy controls (HC) for the levels of these 26 selected potential protein biomarkers. Our SRM data found one protein showing significant difference between SPMS and HC, three proteins differing between SPMS and NIND, two proteins between NIND and HC, and 11 protein biomarkers showing significant difference between a lamotrigine-treated and untreated SPMS group. Principal component analysis (PCA) revealed that these 26 proteins were correlated, and could be represented by four principal components. Overall, we established an efficient platform to develop and verify protein biomarkers in CSF, which can be easily adapted to other proteins of interest related to neurodegenerative diseases.
A highly specific and sensitive multiplex SRM-MS assay was established for development and verification of CSF protein biomarkers in SPMS. Five proteins were found to be expressed significantly differently between the three cohorts, SPMS, NIND and HC and 11 proteins associated with lamotrigine treatment, which we expect will further our current understanding of SPMS disease pathology and/or therapeutic intervention.
PMCID: PMC3466133  PMID: 22846148
21.  Month of birth, vitamin D and risk of immune-mediated disease: a case control study 
BMC Medicine  2012;10:69.
A season of birth effect in immune-mediated diseases (ID) such as multiple sclerosis and type 1 diabetes has been consistently reported. We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB) light exposure and vitamin D status during gestation.
The monthly distribution of births of patients with ID from the UK (n = 115,172) was compared to that of the general population using the Cosinor test. Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient.
The distributions of ID births significantly differed from that of the general population (P = 5e-12) with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P < 0.0001) and a trough in October (odds ratio = 0.945, 95% confidence interval = 0.925, 0.966, P < 0.0001). Stratification by disease subtype showed seasonality in all ID but Crohn's disease. The risk of ID was inversely correlated with predicted second trimester UVB exposure (Spearman's rho = -0.49, P = 0.00005) and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003).
The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID. Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.
PMCID: PMC3395583  PMID: 22764877
22.  Seasonal Distribution of Psychiatric Births in England 
PLoS ONE  2012;7(4):e34866.
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.
PMCID: PMC3319623  PMID: 22496872
23.  Genomic Regions Associated with Multiple Sclerosis Are Active in B Cells 
PLoS ONE  2012;7(3):e32281.
More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (p = 0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (p = 0.00005) and enhancer regions more than expected by chance (strong enhancer p = 0.0006; weak enhancer p = 0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis.
PMCID: PMC3292555  PMID: 22396755
24.  Smoking and Multiple Sclerosis: An Updated Meta-Analysis 
PLoS ONE  2011;6(1):e16149.
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.
Methods/Principal Findings
We performed a Medline search to identify articles published that investigated MS risk following cigarette smoking. A total of 14 articles were included in this study. This represented data on 3,052 cases and 457,619 controls. We analysed these studies in both a conservative (limiting our analysis to only those where smoking behaviour was described prior to disease onset) and non-conservative manner. Our results show that smoking is associated with MS susceptibility (conservative: risk ratio (RR) 1.48, 95% confidence interval (CI) 1.35–1.63, p<10−15; non-conservative: RR 1.52, 95% CI 1.39–1.66, p<10−19). We also analysed 4 studies reporting risk of secondary progression in MS and found that this fell just short of statistical significance with considerable heterogeneity (RR 1.88, 95% CI 0.98–3.61, p = 0.06).
Our results demonstrate that cigarette smoking is important in determining MS susceptibility but the effect on the progression of disease is less certain. Further work is needed to understand the mechanism behind this association and how smoking integrates with other established risk factors.
PMCID: PMC3020969  PMID: 21249154
25.  Geography of hospital admissions for multiple sclerosis in England and comparison with the geography of hospital admissions for infectious mononucleosis: a descriptive study 
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.
Analysis of linked statistical abstracts of hospital data for England between 1999 and 2005.
There were 56 681 MS patients. The admission rate for MS was higher in females (22/105; 95% CI 21.8 to 22.3) than males (10.4/105; 95% CI 10.2 to 10.5). The highest admission rate for MS was seen for residents of Cumbria and Lancashire (North of England) (20.1/105; 95% CI 19.3 to 20.8) and the lowest admission rate was for North West London residents (South of England) (12.4/105; 95% CI 11.8 to 13.1). The geographical distributions of IM and MS were significantly correlated (weighted regression coefficient (r (w))=0.70, p<0.0001). Admission rates for MS were lowest in the area quintile with the highest level of deprivation and they were also lowest in the area quintile with the highest percentage of population born outside the UK. A significant association between northernliness and MS remained after adjustment for deprivation and UK birthplace.
The results show the continued existence of a latitude gradient for MS in England and show a correlation with the distribution of IM. The data have implications for healthcare provision, because lifetime costs of MS exceed £1 million per case in the UK, as well as for studies of disease causality and prevention.
PMCID: PMC3090127  PMID: 21212107

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