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1.  The promise and challenges of blood spot methylomics 
Epigenetics  2013;8(8):775-777.
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.
doi:10.4161/epi.25357
PMCID: PMC3883779  PMID: 23880534
longitudinal studies; epigenetics; blood spot; epigenome wide association study; biomarker
2.  Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies 
Epigenetics  2013;8(4):445-454.
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.
doi:10.4161/epi.24362
PMCID: PMC3674053  PMID: 23538714
BS-seq; buccal; complex disease; epigenome wide association study; human
3.  Weekend admissions as an independent predictor of mortality: an analysis of Scottish hospital admissions 
BMJ Open  2012;2(6):e001789.
Objectives
Weekend admissions have been shown to be associated with an increased risk of mortality compared with weekday admissions for many diagnoses. We analysed emergency department admissions within the Scottish National Health Service to investigate whether mortality is increased in case of weekend emergency department admissions.
Design
A cohort study.
Setting
Scotland National Health Service (NHS) emergency departments.
Participants
5 271 327 emergency department admissions between 1999 and 2009. We included all patients admitted via emergency departments recorded in the Scottish Morbidity Records (SMR01) in NHS, Scotland for whom complete demographic data were available.
Primary outcome measures
Death as recorded by the General Register Office (GRO).
Results
There was a significantly increased probability of death associated with a weekend emergency admission compared with admission on a weekday (unadjusted OR 1.27, 95% CI 1.26 to 1.28, p<0.0001; adjusted for year of admission, gender, age, deprivation quintile and number of comorbidities OR 1.42, 95% CI 1.40 to 1.43, p<0.0001).
Conclusions
Despite a general reduction in mortality over the last 11 years, there is still a significant excess mortality associated with weekend emergency admissions. Further research should be undertaken to identify the precise mechanisms underlying this effect so that measures can be put in place to reduce patient mortality.
doi:10.1136/bmjopen-2012-001789
PMCID: PMC3533021  PMID: 23135542
Accident & Emergency Medicine
4.  Real-world data in the United Kingdom: opportunities and challenges 
BMC Medicine  2016;14:97.
Real-world data is that collected outside the constraints of controlled clinical trials and is increasingly informing decision-making in healthcare. The landscape of real-world data in the United Kingdom is set to evolve over the coming months as the government plans to build on databases currently in place by collecting patient data from all family practices and linking this information with hospital records. This initiative, called care.data, has the potential to be an invaluable resource. However, the programme has been criticized on grounds of data privacy, which has led to an extended delay in its implementation and the expectation that a large number of people will opt out. Opt-outs may introduce substantial biases to the dataset, and understanding how to account for these presents a significant challenge for researchers. For the scope and quality of real-world evidence in the United Kingdom to be realised, and for this information to be used effectively, it is essential to address this challenge.
doi:10.1186/s12916-016-0647-x
PMCID: PMC4921013  PMID: 27342341
Real-world evidence; Care.data; United Kingdom
5.  Decrease in rate of multiple sclerosis-related hospitalizations in Portugal 
F1000Research  2016;5:1353.
We sought to investigate the rate of multiple sclerosis (MS)-related hospitalizations in Portugal and assess whether there have been temporal changes as described in other countries. Using data from the Portuguese National Discharge Registry, we observed that between 2008 and 2013 the rate of MS-related hospitalizations decreased by 44%, from 15.9/100 person-years (95% confidence interval (CI: 14.9-16.9) in 2008 to 8.9/100 person-years (95% CI: 8.2-9.6) in 2013. The change in hospitalization rates is in accordance with what has been observed in other countries, and coincides with the release of new therapies for MS in Portugal.
doi:10.12688/f1000research.8787.1
PMCID: PMC4937828  PMID: 27441085
multiple sclerosis; epidemiology; hospitalizations
6.  The senescent methylome and its relationship with cancer, ageing and germline genetic variation in humans 
Genome Biology  2015;16(1):194.
Background
Cellular senescence is a stable arrest of proliferation and is considered a key component of processes associated with carcinogenesis and other ageing-related phenotypes. Here, we perform methylome analysis of actively dividing and deeply senescent normal human epithelial cells.
Results
We identify senescence-associated differentially methylated positions (senDMPs) from multiple experiments using cells from one donor. We find that human senDMP epigenetic signatures are positively and significantly correlated with both cancer and ageing-associated methylation dynamics. We also identify germline genetic variants, including those associated with the p16INK4A locus, which are associated with the presence of in vivo senDMP signatures. Importantly, we also demonstrate that a single senDMP signature can be effectively reversed in a newly-developed protocol of transient senescence reversal.
Conclusions
The senDMP signature has significant potential for understanding some of the key (epi)genetic etiological factors that may lead to cancer and age-related diseases in humans.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0748-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-015-0748-4
PMCID: PMC4574115  PMID: 26381124
7.  Funding source and primary outcome changes in clinical trials registered on ClinicalTrials.gov are associated with the reporting of a statistically significant primary outcome: a cross-sectional study 
F1000Research  2015;4:80.
Background: We and others have shown a significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. The objectives of this study were to investigate whether changes made to primary outcomes are associated with the likelihood of reporting a statistically significant primary outcome on ClinicalTrials.gov.
Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 20 November 2014 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: 13,238 completed interventional trials were registered with ClinicalTrials.gov that also had study results posted on the website. 2555 (19.3%) had one or more statistically significant primary outcomes. Statistical analysis showed that registration year, funding source and primary outcome change after trial completion were associated with reporting a statistically significant primary outcome .
Conclusions: Funding source and primary outcome change after trial completion are associated with a statistically significant primary outcome report on clinicaltrials.gov.
doi:10.12688/f1000research.6312.2
PMCID: PMC4431380  PMID: 26069729
clinical trials; funding; primary outcome
8.  Funding source and primary outcome changes in clinical trials registered on ClinicalTrials.gov are associated with the reporting of a statistically significant primary outcome: a cross-sectional study 
F1000Research  2015;4:80.
Background: We and others have shown a significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. The objectives of this study were to investigate whether changes made to primary outcomes are associated with the likelihood of reporting a statistically significant primary outcome on ClinicalTrials.gov.
Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 20 November 2014 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: 13,238 completed interventional trials were registered with ClinicalTrials.gov that also had study results posted on the website. 2555 (19.3%) had one or more statistically significant primary outcomes. Statistical analysis showed that registration year, funding source and primary outcome change after trial completion were associated with reporting a statistically significant primary outcome .
Conclusions: Funding source and primary outcome change after trial completion are associated with a statistically significant primary outcome report on clinicaltrials.gov.
doi:10.12688/f1000research.6312.1
PMCID: PMC4431380  PMID: 26069729
clinical trials; funding; primary outcome
9.  Clinical associations between gout and multiple sclerosis, Parkinson’s disease and motor neuron disease: record-linkage studies 
BMC Neurology  2015;15:16.
Background
Uric acid has antioxidant effects on neurons. Abnormally high levels of uric acid are, however, associated with gout. Previous studies have suggested that high levels of uric acid (and the presence of gout) may exert a protective effect against the risk of developing some neurological diseases. We aimed to investigate this hypothesis in a large database of hospital admissions in England.
Methods
We analysed a database of linked statistical records of hospital admissions and death registrations in England (1999–2012). A cohort of people with gout was constructed and followed for development of multiple sclerosis (MS), Parkinson’s disease (PD) or motor neuron disease (MND). Then, conversely, cohorts of all people in the database with MS, PD or MND were constructed and followed for subsequent gout. Rate ratios (RRs) were determined, comparing these cohorts with people in a reference cohort.
Results
In the gout cohort, we observed a modest elevation of the overall risk of subsequent MS, PD and MND (respectively, RR = 1.27 (95% confidence interval 1.03-1.55), 1.11 (1.05-1.17) and 1.28 (1.11-1.48) which was largely attributable to an increased risk observed in the early years after hospitalisation for gout. The increased risk of neurological disease did not remain after 5 years. In the cohorts of people with MS or PD, there was a significantly reduced risk of subsequent gout admission (RR = 0.79 (0.69-0.89) and 0.83 (0.79-0.87), respectively). This inverse association was sustained over time. There was also a reduced risk of MND following gout which only emerged more than five years following initial gout admission (RR at 5+ years 0.35 (0.15-0.68)).
Conclusions
This study investigated the epidemiological evidence for a protective role of high serum concentration of uric acid, for which we used gout as a proxy, in the aetiology of MS, PD or MND. Our observations do not support this hypothesis. However, when the order was reversed, and we retrospectively followed up patients with MS, PD and MND for a number of years, we found a statistically significant deficit of gout. This suggests that there is relationship between some aspects of these neurodegenerative diseases and metabolism of uric acid.
doi:10.1186/s12883-015-0273-9
PMCID: PMC4355134  PMID: 25884318
Multiple sclerosis; Parkinson’s disease; Motor neuron disease; Uric acid; Gout
10.  National survey of UK medical students on the perception of neurology 
BMC Medical Education  2014;14:225.
Background
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.
Methods
A 24 question online survey was designed and distributed in the form of a web-link to all UK medical schools. Responses were collected for 10 weeks with reminders sent at 3 and 6 weeks. A prize-draw of £300 was offered upon completion of the survey.
Results
2877 medical students from 25 of 31 medical schools responded. Students found neurology to be significantly more difficult than other specialties and were least comfortable drawing up a neurological differential diagnosis compared to other specialties (p < 0.0001 for neurology vs. each of the other specialties). Neuroanatomy was regarded as the most important factor contributing to neurology being perceived as difficult.
Conclusions
The findings of the first national survey addressing this issue are consistent with previous research. The perception of neurology remains unchanged, in contrast to the rapidly changing demands of neurological care in an ageing population. Neurological examination and formulating a differential diagnosis are important skills in any medical specialty, and combatting “neurophobia” in medical students is therefore essential.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6920-14-225) contains supplementary material, which is available to authorized users.
doi:10.1186/1472-6920-14-225
PMCID: PMC4295337  PMID: 25335431
National; Survey; Medical education; Neurology; Medical student; Neurological examination
11.  Next generation sequencing in understanding complex neurological disease 
Expert review of neurotherapeutics  2013;13(2):10.1586/ern.12.165.
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, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis etc.). We review current next generation sequencing methodologies and present selected studies illustrating how these have been used to cast light on the genetic aetiology of complex neurological diseases, with specific focus on multiple sclerosis. We 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.
doi:10.1586/ern.12.165
PMCID: PMC3836167  PMID: 23368808
Next generation sequencing; transcriptomics; functional genomics; complex disease; neurological disease
12.  Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-mediated diseases: record-linkage studies 
BMC Neurology  2013;13:176.
Background
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 risk of SAH.
Methods
We 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.
Results
There 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).
Conclusions
Our 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.
doi:10.1186/1471-2377-13-176
PMCID: PMC3833635  PMID: 24229049
13.  Integrating multiple oestrogen receptor alpha ChIP studies: overlap with disease susceptibility regions, DNase I hypersensitivity peaks and gene expression 
BMC Medical Genomics  2013;6:45.
Background
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.
Methods
We integrated multiple oestrogen receptor alpha (ESR1) ChIP datasets in the Genomic Hyperbrowser. We analysed these datasets for overlap with DNase I hypersensitivity peaks, differentially expressed genes with estradiol treatment and regions near single nucleotide polymorphisms associated with sex-related diseases and traits. We used FIMO to scan ESR1 binding sites for classical ESR1 binding motifs drawn from the JASPAR database.
Results
We found that binding sites present in multiple datasets were enriched for classical ESR1 binding motifs, DNase I hypersensitivity peaks and differentially expressed genes after estradiol treatment compared with those present in only few datasets. There was significant enrichment of ESR1 binding present in multiple datasets near genomic regions associated with breast cancer (7.45-fold, p = 0.001), height (2.45-fold, p = 0.002), multiple sclerosis (5.97-fold, p < 0.0002) and prostate cancer (4.47-fold, p = 0.0008), and suggestive evidence of ESR1 enrichment for regions associated with coronary artery disease, ovarian cancer, Parkinson’s disease, polycystic ovarian syndrome and testicular cancer. Integration of multiple cell line ESR1 ChIP datasets also increases overlap with ESR1 ChIP-seq peaks from primary cancer samples, further supporting this approach as helpful in identifying true positive ESR1 binding sites in cell line systems.
Conclusions
Our study suggests that integration of multiple ChIP datasets can highlight binding sites likely to be of particular biological importance and can provide important insights into understanding human health and disease. However, it also highlights the high number of likely false positive binding sites in ChIP datasets drawn from cell lines and illustrates the importance of considering multiple independent experiments together.
doi:10.1186/1755-8794-6-45
PMCID: PMC4228442  PMID: 24171864
14.  Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies 
BMC Medicine  2013;11:171.
Background
Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1741-7015-11-171
PMCID: PMC3729414  PMID: 23885887
Vitamin D; Immune disease; Hospital episode statistics
15.  Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease 
BMC Medicine  2013;11:163.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1741-7015-11-163
PMCID: PMC3710212  PMID: 23849224
Vitamin D; Autoimmune disease; ChIP-seq; Functional genomics
16.  Inactive or moderately active human promoters are enriched for inter-individual epialleles 
Genome Biology  2013;14(5):R43.
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/gb-2013-14-5-r43
PMCID: PMC4053860  PMID: 23706135
Epigenetics; DNA methylation; epialleles
17.  Laparoscopic surgery for Crohn’s disease: a meta-analysis of perioperative complications and long term outcomes compared with open surgery 
BMC Surgery  2013;13:14.
Background
Previous meta-analyses have had conflicting conclusions regarding the differences between laparoscopic and open techniques in patients with Crohn’s Disease. The objective of this meta-analysis was to compare outcomes in patients with Crohn’s disease undergoing laparoscopic or open surgical resection.
Methods
A literature search of EMBASE, MEDLINE, The Cochrane Central Register of Controlled Trials and the US National Institute of Health’s Clinical Trials Registry was completed. Randomized clinical trials and non-randomized comparative studies were included if laparoscopic and open surgical resections were compared. Primary outcomes assessed included perioperative complications, recurrence requiring surgery, small bowel obstruction and incisional hernia.
Results
34 studies were included in the analysis, and represented 2,519 patients. Pooled analysis showed reduced perioperative complications in patients undergoing laparoscopic resection vs. open resection (Risk Ratio 0.71, 95% CI 0.58 – 0.86, P = 0.001). There was no evidence of a difference in the rate of surgical recurrence (Rate Ratio 0.78, 95% CI 0.54 – 1.11, P = 0.17) or small bowel obstruction (Rate Ratio 0.63, 95% CI 0.28 – 1.45, P = 0.28) between techniques. There was evidence of a decrease in incisional hernia following laparoscopic surgery (Rate Ratio 0.24, 95% CI 0.07 – 0.82, P = 0.02).
Conclusions
This is the largest review in this topic. The results of this analysis are based primarily on non-randomized studies and thus have significant limitations in regards to selection bias, confounding, lack of blinding and potential publication bias. Although we found evidence of decreased perioperative complications and incisional hernia in the laparoscopic group, further randomized controlled trials, with adequate follow up, are needed before strong recommendations can be made.
doi:10.1186/1471-2482-13-14
PMCID: PMC3733939  PMID: 23705825
Laparoscopy; Crohn’s disease; Perioperative complications; Surgical recurrence; Hernia; Small bowel obstruction
18.  TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis 
Molecular Medicine  2013;19(1):149-159.
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.
doi:10.2119/molmed.2012.00329
PMCID: PMC3745593  PMID: 23689362
20.  Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies 
BMC Medicine  2013;11:97.
Background
Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB).
Methods
We analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts.
Results
In the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison’s disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture’s syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)).
Conclusions
These two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies.
doi:10.1186/1741-7015-11-97
PMCID: PMC3616814  PMID: 23557090
Hospital episode statistics; Immune disease; Tuberculosis
21.  Correction: Meta-Analysis of the Relationship between Multiple Sclerosis and Migraine 
PLoS ONE  2013;8(4):10.1371/annotation/274e5ef1-79aa-48f7-af62-0594d5c1354e.
doi:10.1371/annotation/274e5ef1-79aa-48f7-af62-0594d5c1354e
PMCID: PMC3613438
22.  Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis 
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.
doi:10.1038/ejhg.2011.197
PMCID: PMC3283173  PMID: 22085902
modeling; multiple SNP analysis; affected sib-pair; IL2RA; multiple sclerosis
23.  Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene 
Neurology  2012;79(5):406-411.
Objective:
To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations.
Methods:
We performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families.
Results:
Four family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; χ2 = 5.76, p = 0.016).
Conclusions:
Rs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. The sequencing of additional family members or other families may help identify other variants important in MS.
doi:10.1212/WNL.0b013e3182616fc4
PMCID: PMC3405256  PMID: 22744673
24.  Risk of fractures in patients with multiple sclerosis: record-linkage study 
BMC Neurology  2012;12:135.
Background
Patients 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.
Methods
We 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.
Results
Significantly 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).
Conclusions
Patients with MS have an increased risk of fractures. Caregivers should aim to optimize bone health in MS patients.
doi:10.1186/1471-2377-12-135
PMCID: PMC3534503  PMID: 23126555
Multiple sclerosis; Fractures; Epidemiology
25.  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.
doi:10.1038/srep00770
PMCID: PMC3480808  PMID: 23105968

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