ORCID Profile
0000-0002-0732-8215
Current Organisation
The University of Edinburgh
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Publisher: Springer Science and Business Media LLC
Date: 09-10-2011
DOI: 10.1038/NG.952
Publisher: Oxford University Press (OUP)
Date: 22-04-2008
DOI: 10.1093/HMG/DDN128
Publisher: Public Library of Science (PLoS)
Date: 12-09-2013
Publisher: Springer Science and Business Media LLC
Date: 25-11-2016
DOI: 10.1038/NCOMMS13507
Abstract: Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP ( RPS6KA2 ) and DMRs ( VMP1, ITGB2 and TXK ) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8 + T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.
Publisher: Oxford University Press (OUP)
Date: 05-05-2009
DOI: 10.1093/HMG/DDP193
Publisher: Elsevier BV
Date: 04-2018
Publisher: Oxford University Press (OUP)
Date: 29-10-2020
Abstract: Historical and emerging data implicate fungi in Crohn’s disease [CD] pathogenesis. However, a causal link between mycobiota, dysregulated immunity, and any impact of NOD2 variants remains elusive. This study aims to evaluate associations between NOD2 variants and faecal mycobiota in CD patients and non-CD subjects. Faecal s les were obtained from 34 CD patients [18 NOD2 mutant, 16 NOD2 wild-type] identified from the UK IBD Genetics Consortium. To avoid confounding influence of mucosal inflammation, CD patients were in clinical remission and had a faecal calprotectin & μg/g 47 non-CD subjects were included as comparator groups, including 22 matched household [four NOD2 mutant] and 25 non-household subjects with known NOD2 genotype [14 NOD2 mutant] identified by the NIHR BioResource Cambridge. Faecal mycobiota composition was determined using internal transcribed spacer 1 [ITS1] sequencing and was compared with 16S rRNA gene sequences and volatile organic compounds. CD was associated with higher numbers of fungal observed taxonomic units [OTUs] [p = 0.033]. Principal coordinates analysis using Jaccard index [p = 0.018] and weighted Bray-Curtis dissimilarities [p = 0.01] showed Candida spp. clustered closer to CD patients whereas Cryptococcus spp. clustered closer to non-CD. In CD, we found higher relative abundance of Ascomycota [p = 0.001] and lower relative abundance Basidiomycota [p = 0.019] phyla. An inverse relationship was found between bacterial and fungal Shannon ersity in NOD2 wild-type which was independent of CD [r = -0.349 p = 0.029]. This study confirms compositional changes in the gut mycobiota in CD and provides evidence that fungi may play a role in CD pathogenesis. No NOD2 genotype-specific differences were observed in the faecal mycobiota.
Publisher: Public Library of Science (PLoS)
Date: 13-01-2011
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2022
DOI: 10.1101/2022.08.16.22278320
Abstract: The progressive nature of Crohn’s disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterise the heterogeneity of disease trajectories in Crohn’s disease by utilising objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn’s disease patients with similar longitudinal faecal calprotectin profiles. Latent class mixed models were used to model faecal calprotectin trajectories within five years of diagnosis and to cluster subjects. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-squared, Fisher’s exact test, and ANOVA were used to test for associations with variables commonly assessed at diagnosis. Our study cohort comprised of 365 patients with newly diagnosed Crohn’s disease and 2856 faecal calprotectin measurements taken within five years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high faecal calprotectin and three clusters characterised by different downward longitudinal trends. Cluster membership was significantly associated with smoking ( p = 0.015), upper gastrointestinal involvement ( p 0.001), and early biologic therapy ( p 0.001). Our analysis demonstrates a novel approach to characterising the heterogeneity of Crohn’s disease by using faecal calprotectin. The group profiles do not simply reflect different treatment regimes and do not mirror classical disease progression endpoints. We believe these profiles represent an entirely new way of classifying disease behaviour in Crohn’s disease.
Publisher: Springer Science and Business Media LLC
Date: 05-01-2015
DOI: 10.1038/NG.3176
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Springer Science and Business Media LLC
Date: 20-07-2015
DOI: 10.1038/NG.3359
Publisher: Elsevier BV
Date: 2016
Publisher: Public Library of Science (PLoS)
Date: 24-02-2014
Publisher: Cold Spring Harbor Laboratory
Date: 10-09-2021
DOI: 10.1101/2021.09.03.21262888
Abstract: It is unclear if people with immune-mediated inflammatory diseases (IMIDs) (joint, bowel and skin) and on immune modifying therapy have increased risk of serious COVID-19 outcomes. With the approval of NHS England we conducted a cohort study, using OpenSAFELY, analysingroutinely-collected primary care data linked to hospital admission, death and previously unavailable hospital prescription data. We used Cox regression (adjusting for confounders) to estimate hazard ratios (HR) comparing risk of COVID-19-death, death/critical care admission, and hospitalisation (March to September 2020) in: 1) people with IMIDs compared to the general population and 2) people with IMIDs on targeted immune modifying drugs (e.g., biologics) compared to standard systemic treatment (e.g., methotrexate). We identified 17,672,065 adults of 1,163,438 (7%) with IMIDs, 19,119 people received targeted immune modifying drugs, and 200,813 received standard systemics. We saw evidence of increased COVID-19-death (HR 1.23, 95%CI 1.20, 1.27), and COVID-19 hospitalisation (HR 1.32, 95%CI 1.29, 1.35) in in iduals with IMIDs overall compared to in iduals without IMIDs of the same age, sex, deprivation and smoking status. We saw no evidence of increased COVID-19 deaths with targeted compared to standard systemic treatments (HR 1.03, 95%CI 0.80, 1.33). There was no evidence of increased COVID-19-related death in those prescribed TNF inhibitors, IL-12/23, IL7, IL-6 or JAK inhibitors compared to standard systemics. Rituximab was associated with increased COVID-19 death (HR 1.68, 95%CI 1.11, 2.56) however, this finding may relate to confounding. COVID-19 death and hospitalisation was higher in people with IMIDs. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune modifying drugs for IMIDs compared to standard systemics. We searched PubMed on May 19 th , 2021, using the terms “COVID-19”, “SARS-CoV-2” and “rheumatoid arthritis”, “psoriatic arthritis” “ankylosing spondylitis”, “Crohn’s disease” “ulcerative colitis” “hidradenitis suppurativa” and “psoriasis”, to identify primary research articles examining severe COVID-19 outcome risk in in iduals with immune-mediated inflammatory diseases (IMIDs) and those on immune modifying therapy. The studies identified (including matched cohort studies and studies in disease-specific registries) were limited by small s le sizes and number of outcomes. Most studies did not show a signal of increased adverse COVID-19 outcomes in those on targeted therapies, with the exception of rituximab. Additionally, disease-specific registries are subject to selection bias and lack denominator populations. In our large population-based study of 17 million in iduals, including 1 million people with IMIDs and just under 200,000 receiving immune modifying medications, we saw evidence that people with IMIDs had an increased risk of COVID-19-related death compared to the general population after adjusting for potential confounders (age, sex, deprivation, smoking status) (HR 1.23, 95%CI 1.20, 1.27). We saw differences by IMID type, with COVID-19-related death being increased by the most in people with inflammatory joint disease (HR 1.47, 95%CI 1.40, 1.54). We also saw some evidence that those with IMIDs were more likely, compared to the general population, to have COVID-19-related critical care admission/death (HR 1.24, 95%CI 1.21, 1.28) and hospitalisation (HR 1.32, 95%CI 1.29, 1.35). Compared to people with IMIDs taking standard systemics, we saw no evidence of differences in severe COVID-19-related outcomes with TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-6 inhibitors and JAK inhibitors. However, there was some evidence that rituximab was associated with an increased risk of COVID-19-related death (HR 1.68, 95%CI 1.11, 2.56) and death/critical care admission (HR 1.92, 95%CI 1.31, 2.81). We also saw evidence of an increase in COVID-19-related hospital admissions in people prescribed rituximab (HR 1.59, 95%CI 1.16, 2.18) or JAK inhibition (HR 1.81, 95%CI 1.09, 3.01) compared to those on standard systemics, although this could be related to worse underlying health rather than the drugs themselves, and numbers of events were small. This is the first study to our knowledge to use high-cost drug data on medicines supplied by hospitals at a national scale in England (to identify targeted therapies). The availability of these data fills an important gap in the medication record of those with more specialist conditions treated by hospitals creating an important opportunity to generate insights to these conditions and these medications Our study offers insights into future risk mitigation strategies and SARS-CoV-2 vaccination priorities for in iduals with IMIDs, as it highlights that those with IMIDs and those taking rituximab may be at risk of severe COVID-19 outcomes. Critically, our study does not show a link between most targeted immune modifying medications compared to standard systemics and severe COVID-19 outcomes. However, the increased risk of adverse COVID-19 outcomes that we saw in people with IMIDs and those treated with rituximab merits further study.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2008
DOI: 10.1038/NG.145
Publisher: BMJ
Date: 11-07-2019
DOI: 10.1136/GUTJNL-2019-318936
Abstract: IBD prevalence is estimated to be rising, but no detailed, recent UK data are available. The last reported prevalence estimate in the UK was 0.40% in 2003. We aimed to establish the current, and project future, prevalence in Lothian, Scotland. We conducted an all-age multiparameter search strategy using inpatient IBD international classification of disease (ICD-10) coding (K50/51)(1997–2018), IBD pathology coding (1990–2018), primary and secondary care prescribing data (2009–2018) and a paediatric registry, (1997–2018) to identify ‘possible’ IBD cases up to 31/08/2018. Diagnoses were manually confirmed through electronic health record review as per Lennard-Jones/Porto criteria. Autoregressive integrated moving average (ARIMA) regression was applied to forecast prevalence to 01/08/2028. In total, 24 601 possible IBD cases were identified of which 10 499 were true positives. The point prevalence for IBD in Lothian on 31/08/2018 was 784/100 000 (UC 432/100 000, Crohn’s disease 284/100 000 and IBD unclassified (IBDU) 68/100 000). Capture–recapture methods identified an additional 427 ‘missed’ cases (95% CI 383 to 477) resulting in a ‘true’ prevalence of 832/100 000 (95% CI 827 to 837). Prevalence increased by 4.3% per year between 2008 and 2018 (95% CI +3.7 to +4.9%, p .0001). ARIMA modelling projected a point prevalence on 01/08/2028 of 1.02% (95% CI 0.97% to 1.07%) that will affect an estimated 1.53% (95% CI 1.37% to 1.69%) of those years of age. We report a rigorously validated IBD cohort with all-age point prevalence on 31/08/2018 of 1 in 125, one of the highest worldwide.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2008
DOI: 10.1038/NG.140
Publisher: Springer Science and Business Media LLC
Date: 10-05-2009
DOI: 10.1038/NG.361
Publisher: Wiley
Date: 19-02-2016
DOI: 10.1111/APT.13547
Publisher: Springer Science and Business Media LLC
Date: 06-06-2007
DOI: 10.1038/NG2061
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1038/MI.2017.74
Publisher: Oxford University Press (OUP)
Date: 16-02-2018
DOI: 10.1093/IBD/IZX061
Publisher: Springer Science and Business Media LLC
Date: 09-01-2017
DOI: 10.1038/NG.3761
Publisher: Springer Science and Business Media LLC
Date: 31-10-2012
DOI: 10.1038/NATURE11582
Publisher: Springer Science and Business Media LLC
Date: 21-11-2010
DOI: 10.1038/NG.717
Publisher: Springer Science and Business Media LLC
Date: 14-09-2008
DOI: 10.1038/NG.218
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
Publisher: Springer Science and Business Media LLC
Date: 21-06-2018
DOI: 10.1038/S41467-018-04365-8
Abstract: GWAS have identified risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis -eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger s le sizes will be required to demonstrate the causality of in idual genes using this approach.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Charlie Lees.