Publications
37 results found
Berlanga A, Cupp M, Tzoulaki I, et al., 2020, Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies, BMC Medicine, Vol: 18, ISSN: 1741-7015
BackgroundAlthough neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. We aimed to evaluate the strength and validity of evidence on the association between either the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis.MethodsWe searched MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to 29 May 2020 for systematic reviews and meta-analyses of observational studies on neutrophil counts (here NLR or TAN) and specific cancer outcomes related to disease progression or survival. The available evidence was graded as strong, highly suggestive, suggestive, weak or uncertain through the application of pre-set GRADE criteria.ResultsA total of 204 meta-analyses from 86 studies investigating the association between either NLR or TAN and cancer outcomes met the criteria for inclusion. All but one meta-analyses found a hazard ratio (HR) which increased risk (HR > 1). We did not find sufficient meta-analyses to evaluate TAN and cancer outcomes (N = 9). When assessed for magnitude of effect, significance and bias related to heterogeneity and small study effects, 18 (9%) associations between NLR and outcomes in composite cancer endpoints (combined analysis), cancers treated with immunotherapy and some site specific cancers (urinary, nasopharyngeal, gastric, breast, endometrial, soft tissue sarcoma and hepatocellular cancers) were supported by strong evidence.ConclusionIn total, 60 (29%) meta-analyses presented strong or highly suggestive evidence. Although the NLR and TAN hold clinical promise in their association with poor cancer prognosis, further research is required to provide robust evidence, assess causality and test clinical utility.
Romo-García MF, Bastian Y, Zapata-Zuñiga M, et al., 2019, Identification of putative miRNA biomarkers in early rheumatoid arthritis by genome-wide microarray profiling: A pilot study, Gene, Vol: 720, ISSN: 0378-1119
Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA.When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR361-5p, identifying this miRNA as a potential biomarker of disease.We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use.
Romo-Garcia MF, Bastian Y, Zapata-Zuniga M, et al., 2019, miRNAs expression profile in early rheumatoid arthritis and validation of hsa-miR-361-5p as biomarker for early diagnosis, 17th International Congress of Immunology of the International-Union-of-Immunological-Societies (IUIS), Publisher: WILEY, Pages: 262-263, ISSN: 0014-2980
Cribbs A, Heger A, Luna-Valero S, et al., 2019, cgat-developers/cgat-core: 0.5.15
tidy up error handling. Allow memory issues with SLURM to pass through.
Cribbs AP, Luna-Valero S, George C, et al., 2019, CGAT-core: a python framework for building scalable, reproducible computational biology workflows, F1000Research, Vol: 8, Pages: 377-377
<ns4:p>In the genomics era computational biologists regularly need to process, analyse and integrate large and complex biomedical datasets. Analysis inevitably involves multiple dependent steps, resulting in complex pipelines or workflows, often with several branches. Large data volumes mean that processing needs to be quick and efficient and scientific rigour requires that analysis be consistent and fully reproducible. We have developed CGAT-core, a python package for the rapid construction of complex computational workflows. CGAT-core seamlessly handles parallelisation across high performance computing clusters, integration of Conda environments, full parameterisation, database integration and logging. To illustrate our workflow framework, we present a pipeline for the analysis of RNAseq data using pseudo-alignment.</ns4:p>
Aldapa-Vega G, Moreno-Eutimio MA, Berlanga-Taylor A, et al., 2019, Structural variants of Salmonella Typhimurium lipopolysaccharide induce less dimerization of TLR4/MD-2 and reduced pro-inflammatory cytokine production in human monocytes, Molecular Immunology, Vol: 111, Pages: 43-52, ISSN: 0161-5890
Salmonella enterica serovar Typhimurium (S. Typhimurium) changes the structure of its lipopolysaccharide (LPS) in response to the environment. The two main LPS variants found in S. Typhimurium correspond to LPS with a hepta-acylated lipid A (LPS 430) and LPS with modified phosphate groups on its lipid A (LPS 435). We have previously shown that these modified LPS have a lower capacity than wild type (WT) LPS to induce the production of pro-inflammatory cytokines in mice. Nevertheless, it is not know if LPS 430 and LPS 435 could also subvert the innate immune responses in human cells. In this study, we found that LPS 430 and LPS 435 were less efficient than WT LPS to induce the production of pro-inflammatory cytokines by human monocytes, in addition we found a decreased dimerization of the TLR4/MD-2 complex in response to LPS 430, suggesting that structurally modified LPS are sensed differently than WT LPS by this receptor; however, LPS 430 and 435 induced similar activation of the transcription factors NF-κB p65, IRF3, p38 and ERK1/2 than WT LPS. Microarray analysis of LPS 430- and LPS 435-activated monocytes revealed a gene transcription profile with differences only in the expression levels of microRNA genes compared to the profile induced by WT LPS, suggesting that the lipid A modifications present in LPS 430 and LPS 435 have a moderate effect on the activation of the human TLR4/MD-2 complex. Our results are relevant to understand LPS modulation of immune responses and this knowledge could be useful for the development of novel adjuvants and immunomodulators.
Cribbs A, Heger A, Luna-Valero S, et al., 2019, cgat-developers/cgat-core: 0.5.14
Core functionality of the CGAT code
Cribbs A, Heger A, Luna-Valero S, et al., 2019, cgat-developers/cgat-core: Basic cloud functionality
In this release we include basic functionality to allow users to interact with Amazon S3, Google Cloud and Azure storage objects.
Berlanga A, 2019, AntonioJBT/project_quickstart: cgatcore 0.5.13 plus minor bugs
Boilerplate tools and templates for setting up a data analysis project.
Berlanga A, 2019, episcout
R software package which facilitates cleaning, exploring and visualising large epidemiological data-sets.
Cariolou M, Cupp M, Evangelou E, et al., 2019, Importance of vitamin D in critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis, BMJ Open, Vol: 9, ISSN: 2044-6055
Background: Critical care and sepsis remain high priority concerns in children. Observational studies report high prevalence of vitamin D deficiency and present mixed results regarding the correlation between vitamin D status and adverse outcomes. Associations between deficiency and mortality, particularly in children with sepsis, remain unclear. We performed a systematic review and meta-analysis to address this uncertainty. Methods: PubMed, OVID and Google Scholar were searched for observational studies in critically ill children. We obtained pooled prevalence estimates for vitamin D deficiency and odds ratios for the association of mortality in critically ill children treated in intensive care units, with subgroup analysis for those with sepsis and those with respiratory tract infections. Meta-regression and sensitivity analyses were used to investigate heterogeneity. Findings: Forty-eight studies were included. The total sample size was 7,199, with 1,679 (23%) children acting as controls in case-control studies. Of 5,520 critically ill children, 2,664 (48%) were vitamin D deficient (< 50 nmol/L). Results of the random effects model demonstrated a pooled prevalence of vitamin D deficiency of 54.9% (95% CI 48.0-61.6, I 2 =95.0%, 95% CI 94.0-95.8, p < 0.0001). In subgroup analysis of children with sepsis (16 studies, 788 total individuals) we observed higher prevalence of deficiency (63.8%, 95% CI 49.9-75.7, I 2 =90.5%, 95% CI 86.2-93.5%, p < 0.0001). In patients admitted for respiratory tract infections (24 studies, 1,683 total individuals), prevalence was 49.9% (95% CI 37.6-62.2; I 2 = 93.9%, 95% CI 92.1-95.3, p < 0.0001). Only one identified study assessed vitamin D levels in sepsis and mortality. The meta-regression model with all available variables (year of publication, total study sample size, quality score, study design, country group and clinical setting) explained 37.52% of I 2 (F = 5.1119, p = 0.0005) with clinical setting and country groups b
Cribbs A, Luna-Valero S, George C, et al., 2019, cgat-developers/cgat-core: First public release of code
This release was created for the first submission of the manuscript accompanying this code
Cribbs A, Luna-Valero S, George C, et al., 2019, CGAT-core: a python framework for building scalable, reproducible computational biology workflows
<jats:p>In the genomics era computational biologists regularly need to process, analyse and integrate large and complex biomedical datasets. Analysis inevitably involves multiple dependent steps, resulting in complex pipelines or workflows, often with several branches. Large data volumes mean that processing needs to be quick and efficient and scientific rigour requires that analysis be consistent and fully reproducible. We have developed CGAT-core, a python package for the rapid construction of complex computational workflows. CGAT-core seamlessly handles parallelisation across high performance computing clusters, integration of Conda environments, full parameterisation, database integration and logging. To illustrate our workflow framework, we present a pipeline for the analysis of RNAseq data using pseudo-alignment.</jats:p>
Cribbs AP, Luna-Valero S, George C, et al., 2019, CGAT-core: A python framework for building scalable, reproducible computational biology workflows., F1000Research, Vol: 8
In the genomics era computational biologists regularly need to process, analyse and integrate large and complex biomedical datasets. Analysis inevitably involves multiple dependent steps, resulting in complex pipelines or workflows, often with several branches. Large data volumes mean that processing needs to be quick and efficient and scientific rigour requires that analysis be consistent and fully reproducible. We have developed CGAT-core, a python package for the rapid construction of complex computational workflows. CGAT-core seamlessly handles parallelisation across high performance computing clusters, integration of Conda environments, full parameterisation, database integration and logging. To illustrate our workflow framework, we present a pipeline for the analysis of RNAseq data using pseudo-alignment.
Berlanga A, 2018, AntonioJBT/project_quickstart: added tests, flake8, and minor updates
Boilerplate tools and templates for setting up a data analysis project.
Cupp M, Cariolou M, Tzoulaki I, et al., 2018, Neutrophil counts and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies, National-Cancer-Research-Institute (NCRI) Cancer Conference, Publisher: NATURE PUBLISHING GROUP, Pages: 26-27, ISSN: 0007-0920
Berlanga-Taylor AJ, 2018, From Identification to Function: Current Strategies to Prioritise and Follow-Up GWAS Results., Methods Mol Biol, Vol: 1793, Pages: 259-275
Along with family-based studies, dozens of genome-wide association studies (GWAS) have clearly identified the genetic basis of common diseases and complex traits. There are currently hundreds of single nucleotide polymorphisms (SNP) associated with human disease as well as biochemical and physiological phenotypes. Although this is only the tip of the iceberg, we are now confronted with a general lack of understanding of how these trait-associated variants act. How do these genetic changes lead to overt clinical phenotypes? What are the molecular mechanisms? Can we harness this information to develop better preventive and curative strategies? Current efforts are shifting to focus on these questions as we move from identifying variants to understanding their effects. Here I provide a broad overview of the main technical concerns and current bottlenecks as we approach this new phase.
Berlanga-Taylor AJ, Plant K, Dahl A, et al., 2018, Genomic response to vitamin D supplementation in the setting of a randomized, placebo-controlled trial, EBioMedicine, Vol: 31, Pages: 133-142, ISSN: 2352-3964
BACKGROUND: Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomized trials may afford an opportunity to systematically assess molecular responses. METHODS: In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), a double-blind, placebo-controlled, dose-finding, randomized clinical trial, 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D3 4000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) at baseline and after 12 months, were measured. The trial had >90% power to detect 1.2-fold changes in gene expression. FINDINGS: Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D, 4000 IU regimen), but had no significant effect on whole-blood gene expression (FDR < 5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose, but not in the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose). No significant associations involving vitamin D supplementation response eQTLs were found. INTERPRETATION: We performed a comprehensive functional genomics and molecular analysis of vitamin D supplementation in a randomized, placebo-controlled trial. Although this study was limited to mostly Caucasian individuals aged over 65 years, the results differ from many previous studi
Berlanga-Taylor A, Plant K, Lau E, et al., 2017, Effect of vitamin D supplementation on biomarkers of inflammation and immune function: functional genomics analysis of the BEST-D trial, Publisher: bioRxiv
Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomised trials may afford an opportunity to systematically assess molecular responses to treatments. In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D3 4000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) were measured at baseline and after 12 months. The trial had >90% power to detect a 2-fold change in gene expression. Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D), but had no significant effect on whole-blood gene expression (FDR <5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose but not on the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose), but had no significant effect on cis-eQTLs specific to vitamin D supplementation. The trial demonstrates the feasibility of application of functional genomics approaches in randomised trials to assess the effects of vitamin D on immune function. Clinical Trial Registration: ISRCTN #07034656; EudraCT #2011-005763-24.
Gallone G, Haerty W, Disanto G, et al., 2017, Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease, Human Molecular Genetics, Vol: 26, Pages: 2164-2176, ISSN: 1460-2083
Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (>2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn’s disease and rheumatoid arthritis. The approach’s validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.
Gallone G, Haerty W, Disanto G, et al., 2017, Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease, Publisher: Oxford University Press (OUP)
Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR) whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (> 2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. The approach's validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.
Berlanga A, 2014, CGAT: computational genomics analysis toolkit
CGAT Apps is a collection of scripts to analyse high-throughput sequencing data. See publication in: https://academic.oup.com/bioinformatics/article/30/9/1290/234582See full list of contributors in:https://github.com/cgat-developers/cgat-apps/graphs/contributors
Elangovan RI, Disanto G, Berlanga-Taylor AJ, et al., 2014, Regulatory genomic regions active in immune cell types explain a large proportion of the genetic risk of multiple sclerosis., J Hum Genet, Vol: 59, Pages: 211-215
There is little understanding of how genetic variants discovered in recent genome-wide association studies are involved in the pathogenesis of multiple sclerosis (MS). We aimed to investigate which chromatin states and cell types explain genetic risk in MS. We used genotype data from 1854 MS patients and 5164 controls produced by the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium. We estimated the proportion of phenotypic variance between cases and controls explained by cell-specific chromatin state and DNase I hypersensitivity sites (DHSs) using the Genome-wide Complex Trait Analysis software. A large proportion of variance was explained by single-nucleotide polymorphisms (SNPs) in strong enhancer (SE) elements of immortalized B lymphocytes (5.39%). Three independent SNPs located within SE showed suggestive evidence of association with MS: rs12928822 (odds ratio (OR)=0.81, 95% confidence interval (CI)=0.73-0.89, P=2.48E-05), rs727263 (OR=0.75, 95% CI=0.66-0.85, P=3.26E-06) and rs4674923 (OR=0.85, 95% CI=0.79-0.92, P=1.63E-05). Genetic variants located within DHSs of CD19+ B cells explained the greatest proportion of variance. Genetic variants influencing the risk of MS are located within regulatory elements active in immune cells. This study also identifies a number of immune cell types likely to be involved in the causal cascade and that carry important implications for future studies of therapeutic design.
Berlanga-Taylor AJ, Knight JC, 2014, An Integrated Approach to Defining Genetic and Environmental Determinants for Major Clinical Outcomes Involving Vitamin D, Molecular Diagnosis and Therapy, Vol: 18, Pages: 261-272, ISSN: 1177-1062
There is substantial genetic and epidemiologicalevidence implicating vitamin D in the pathogenesis ofmany common diseases. A number of studies have soughtto define an association for disease with sequence variationin the VDR gene, encoding the ligand-activated nuclearhormone receptor for vitamin D. The results of such studieshave been difficult to replicate and are likely to need toaccount for specific environmental exposures. Here, wereview recent work that has begun to study the interactionsbetween VDR gene polymorphisms, vitamin D blood levels,and complex disease susceptibility, notably in thecontext of major clinical outcomes. We highlight thechallenges moving forward in this area and its importancefor effective clinical translation of current research.
Disanto G, Kjetil Sandve G, Ricigliano VAG, et al., 2014, DNase hypersensitive sites and association with multiple sclerosis., Hum Mol Genet, Vol: 23, Pages: 942-948
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.
Sims D, Ilott NE, Sansom SN, et al., 2014, CGAT: computational genomics analysis toolkit, Bioinformatics, Vol: 30, Pages: 1290-1291, ISSN: 1367-4803
Summary: Computational genomics seeks to draw biological inferences from genomic datasets, often by integrating and contextualizing next-generation sequencing data. CGAT provides an extensive suite of tools designed to assist in the analysis of genome scale data from a range of standard file formats. The toolkit enables filtering, comparison, conversion, summarization and annotation of genomic intervals, gene sets and sequences. The tools can both be run from the Unix command line and installed into visual workflow builders, such as Galaxy.
Disanto G, Hall C, Lucas R, et al., 2013, Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis., Mult Scler, Vol: 19, Pages: 1355-1358
Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.
Handel AE, Sandve GK, Disanto G, et al., 2013, Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease, BMC Medicine, Vol: 11, ISSN: 1741-7015
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 m
Berlanga-Taylor AJ, Ramagopalan SV, 2013, Vitamin D and multiple sclerosis: what is the clinical impact?, Expert Opin Med Diagn, Vol: 7, Pages: 227-229
Evidence for a causal role for vitamin D in multiple sclerosis (MS) is being gathered. Epidemiological, molecular and animal model studies have paved the way in our understanding of the effects of vitamin D in demyelinating disease. Several clinical trials have been completed and more are under way to understand the full extent and value of vitamin D supplementation on disease progression. Many questions remain unanswered however and careful study design is increasingly pertinent. Timing of exposure, dosage and transgenerational effects are some of the several important questions that need to be addressed. In this issue, Carlson and Rose highlight these points and provide a review of vitamin D and MS with an emphasis on the most recent clinical studies. Further evidence of vitamin D deficiency as a causal factor, its molecular targets in MS and its prospect as a therapeutic and preventative agent are questions that warrant further study.
Disanto G, Sandve GK, Berlanga-Taylor AJ, et al., 2012, Vitamin D receptor binding, chromatin states and association with multiple sclerosis., Human Molecular Genetics, Vol: 21, Pages: 3575-3586, ISSN: 0964-6906
Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. However, how these factors interact in disease causation is unclear. We aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid cell lines (LCLs), chromatin states in LCLs and MS-associated genomic regions. Using the Genomic Hyperbrowser, we found that VDR-binding regions overlapped with active regulatory regions [active promoter (AP) and strong enhancer (SE)] in LCLs more than expected by chance [45.3-fold enrichment for SE (P < 2.0e-05) and 63.41-fold enrichment for AP (P < 2.0e-05)]. Approximately 77% of VDR regions were covered by either AP or SE elements. The overlap between VDR binding and regulatory elements was significantly greater in LCLs than in non-immune cells (P < 2.0e-05). VDR binding also occurred within MS regions more than expected by chance (3.7-fold enrichment, P < 2.0e-05). Furthermore, regions of joint overlap SE-VDR and AP-VDR were even more enriched within MS regions and near to several disease-associated genes. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS regions. Furthermore, the data provide additional evidence for an important role played by B cells in MS. Further analyses in other immune cell types and functional studies are warranted to fully elucidate the role of vitamin D in the immune system.
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