Simon Broadley

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

To perform a 1‐stage meta‐analysis of genome‐wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.

MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood.

It is well established that Multiple Sclerosis (MS) is an immune mediated disease. Little is known about what drives the differential control of the immune system in MS patients compared to unaffected individuals. MicroRNAs (miRNAs) are small non-coding nucleic acids that are involved in the control of gene expression. Their potential role in T cell activation and neurodegenerative disease has recently been recognised and they are therefore excellent candidates for further studies in MS. We investigated the transcriptome of currently known miRNAs using miRNA microarray analysis in peripheral blood samples of 59 treatment naïve MS patients and 37 controls. Of these 59, 18 had a primary progressive, 17 a secondary progressive and 24 a relapsing remitting disease course. In all MS subtypes miR-17 and miR-20a were significantly under-expressed in MS, confirmed by RT-PCR. We demonstrate that these miRNAs modulate T cell activation genes in a knock-in and knock-down T cell model. The same T cell activation genes are also up-regulated in MS whole blood mRNA, suggesting these miRNAs or their analogues may provide useful targets for new therapeutic approaches.

A genome screen for multiple sclerosis in Sardinian multiplex families.

The prevalence of multiple sclerosis in Sardinia is significantly higher than in neighbouring Mediterranean countries, suggesting that the isolated growth of the population has concentrated genetic factors which increase susceptibility to the disease. The distinct HLA association of multiple sclerosis in Sardinia supports this interpretation. We have performed a whole genome screen for linkage in 49 Sardinian multiplex families using 327 markers. Non parametric linkage analysis of these data reveal suggestive linkage in the region of Chr 1q31, Chr 10q23 and Chr 11p15.

Predictors of prolonged dysphagia following acute stroke

Dysphagia following acute stroke frequently necessitates prolonged enteral feeding. There is evidence that early enteral feeding via percutaneous endoscopic gastrostomy (PEG) is both beneficial and safe. The aim of this study was to identify predictors of prolonged dysphagia. The subjects were 149 consecutive patients admitted with acute stroke. Clinical findings and imaging results were prospectively collected, and subsequent progress recorded. Subjects were divided into 3 groups for analysis: no dysphagia; transient dysphagia (< or =14 days); or prolonged dysphagia (>14 days). Validity of the water swallow test as a predictor of aspiration pneumonia was confirmed. Significant associations for prolonged dysphagia were seen with stroke severity, dysphasia and lesions of the frontal and insular cortex on brain imaging. These results indicate that it may be possible to predict patients who will develop prolonged significant dysphagia following acute stroke thereby facilitating referral for insertion of PEG at an earlier time point.

A genome screen for multiple sclerosis in Italian families

We have screened the whole genome for linkage in 40 Italian multiplex families with multiple sclerosis using 322 markers. The GENEHUNTER-PLUS program was used to analyse these data and revealed eight regions of potential linkage where the lod score exceeds the nominal 5% significance level (0.7). No region of linkage with genome-wide significance was identified and none of the markers showed evidence of statistically significant transmission disequilibrium. Overall these results have refined the linkage data relating to this disease in Italians modestly supporting some previously identified areas of interest and helping to exclude others.

The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.

Early investigation and treatment of obstructive sleep apnoea after acute stroke

Obstructive sleep apnoea (OSA) is an independent risk factor for hypertension, which is a major cause of stroke. The prevalence and associations of OSA in a cohort of stroke patients were studied. The safety and tolerability of early treatment with nasal continuous airways pressure (nCPAP) was also assessed. Consecutive subjects admitted with acute stroke were assessed clinically, radiologically and with scales assessing prior OSA risk, dysphagia and disability. Sleep studies were performed within the first few days of admission using a portable diagnostic system. Twenty-nine of 55 (53%) subjects had evidence of OSA, using an apnoea-hypopnoea index (AHI) of 10 or greater. The AHI was significantly associated with an index of prior OSA symptoms, but not with history of hypertension, degree of dysphagia, or type and severity of stroke. Use of a portable diagnostic system for detecting OSA in the acute stroke setting was well tolerated. OSA is common after acute stroke and exceeds rates seen in control populations of similar age (53% vs. 11%). Early treatment with nCPAP was effective and well tolerated.

SUNCT and SUNA: Clinical features and medical treatment

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are considered to be rare primary headache disorders. The purpose of this study was to define the clinical features, response to prophylactic treatment and efficacy of lignocaine by subcutaneous infusion for periods of acute exacerbation requiring hospitalisation. Over a period of 6 years (March 2000--February 2006) all cases of SUNCT and SUNA in neurology clinics at the Gold Coast Hospital, Australia, were reviewed. International Headache Society diagnostic criteria were used. Clinical features and response to treatment were prospectively recorded using headache diaries and magnetic resonance imaging of the brain was carried out. Twenty-four subjects with SUNCT or SUNA were identified. The incidence of these conditions was 1.2/100,000 and the prevalence 6.6/100,000. An episodic disease course was evident in 14/24 (58%) cases, whereas 10/24 (42%) had a chronic course. An aberrant vessel in close association with the fifth cranial nerve was seen in 88% of cases. A good or excellent response to lamotrigine was seen in 11/19 (58%) and was more effective in the episodic group (100%). A subcutaneous infusion of lignocaine proved completely effective on 11/14 (78%) occasions. SUNCT and SUNA are not rare conditions. Characterisation into episodic and chronic disease course appears to be of prognostic and therapeutic importance. Lamotrigine is effective in the majority of cases and subcutaneous lignocaine is useful as acute treatment for severe recalcitrant attacks.

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

BACKGROUND Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V

Modelling Genetic Susceptibility to Multiple Sclerosis with Family Data

KROX_Q6, p-value <3.31E-6; V