Sreeram V Ramagopalan

DNase hypersensitive sites and association with multiple sclerosis

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.

Association of vitamin D and multiple sclerosis in India

Background: 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. Objective: The objective of this paper is to determine whether vitamin D status is associated with MS in India. Methods: In this study 110 MS patients and 108 matched controls were included. Serum 25-hydroxyvitamin D (25(OH)D) was measured in 63 patients in relapse, 77 patients in remission and all controls. Quantity of sun exposure in childhood and body mass index (BMI) were calculated. Patients and controls were genotyped for HLA-DRB1*1501. Results: Patients had significantly lower 25(OH)D levels than matched controls (p = 0.003), and patients in relapse had a significantly lower vitamin D level as compared to those in remission (p = 0.001). Vitamin D deficiency (< 50 nmol/l) was seen in a higher proportion of cases (71.8%) than controls (53.7%) (p = 0.01). Higher quartiles of vitamin D (> 58 nmol/l) showed an inverse relationship with MS (OR = 0.28, CI = 0.11–0.68, p= 0.005). This effect persisted after adjusting for sun exposure. Conclusion: The results of our study indicated that serum 25(OH)D shows an inverse relationship with MS in the Indian population. Reverse causality cannot be excluded.

Risk of fractures in patients with multiple sclerosis: record-linkage study

BackgroundPatients with multiple sclerosis (MS) have been reported to be at higher risk of fracture than other people. We sought to test this hypothesis in a large database of hospital admissions in England.MethodsWe analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999–2010). Rate ratios for fractures were determined, comparing fracture rates in a cohort of all people in England admitted with MS and rates in a comparison cohort.ResultsSignificantly elevated risk for all fractures was found in patients with MS (rate ratio (RR) = 1.99, 95% confidence interval (CI) = 1.93-2.05)). Risks were particularly high for femoral fractures (femoral neck fracture RR = 2.79 (2.65-2.93); femoral shaft fracture RR 6.69 (6.12-7.29)), and fractures of the tibia or ankle RR = 2.81 (2.66-2.96).ConclusionsPatients with MS have an increased risk of fractures. Caregivers should aim to optimize bone health in MS patients.

Prevalence of primary outcome changes in clinical trials registered on ClinicalTrials.gov: a cross-sectional study.

Background: 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. Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 25 October 2012 was performed. The main outcome was any change made to the initially listed primary outcome and the time of the change in relation to the trial start and end date. Findings: Our analysis showed that 28229 of 89204 (31.7%) registered studies had their primary outcome changed. Industry funding was associated with all primary outcome changes, odds ratio (OR)= 1.36, 95% confidence interval (CI)=1.31-1.41, p<0.001; with primary outcome changes after study start date OR=1.37, 95% CI=1.32-1.42, p<0.001; with primary outcome changes after primary completion date OR=1.84, 95% CI=1.75-1.94, p<0.001 and with primary outcome changes after study completion date OR=1.82, 95% CI=1.73-1.91, p<0.001. Conclusions A significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. These changes are associated with funding source.

Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-mediated diseases: record-linkage studies.

BackgroundSubarachnoid 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 risk of SAH.MethodsWe analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999–2011). Rate ratios for SAH were determined, comparing immune-mediated disease cohorts with comparison cohorts.ResultsThere were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison’s disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn’s disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, SLE and thyrotoxicosis. Elevated risks that were greater than 2-fold were found for Addison’s disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura (RR = 2.42, 1.86-3.11), primary biliary cirrhosis (RR = 2.21, 1.43-3.16) and SLE (RR = 3.76, 3.08-4.55).ConclusionsOur findings strongly support the suggestion that patients with some immune-mediated diseases have an increased risk of SAH. Further studies of the mechanisms behind this association are warranted.