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A Meta-Analysis of Public Microarray Data Identifies Gene Regulatory Kröger et al. BMC Medical Genomics (2016) 9:66 DOI 10.1186/s12920-016-0227-0 RESEARCH ARTICLE Open Access A meta-analysis of public microarray data identifies gene regulatory pathways deregulated in peripheral blood mononuclear cells from individuals with Systemic Lupus Erythematosus compared to those without Wendy Kröger*, Darlington Mapiye, Jean-Baka Domelevo Entfellner and Nicki Tiffin Abstract Background: Systemic Lupus Erythematosus (SLE) is a complex, multi-systemic, autoimmune disease for which the underlying aetiological mechanisms are poorly understood. The genetic and molecular processes underlying lupus have been extensively investigated using a variety of -omics approaches, including genome-wide association studies, candidate gene studies and microarray experiments of differential gene expression in lupus samples compared to controls. Methods: This study analyses a combination of existing microarray data sets to identify differentially regulated genetic pathways that are dysregulated in human peripheral blood mononuclear cells from SLE patients compared to unaffected controls. Two statistical approaches, quantile discretisation and scaling, are used to combine publicly available expression microarray datasets and perform a meta-analysis of differentially expressed genes. Results: Differentially expressed genes implicated in interferon signaling were identified by the meta-analysis, in agreement with the findings of the individual studies that generated the datasets used. In contrast to the individual studies, however, the meta-analysis and subsequent pathway analysis additionally highlighted TLR signaling, oxidative phosphorylation and diapedesis and adhesion regulatory networks as being differentially regulated in peripheral blood mononuclear cells (PBMCs) from SLE patients compared to controls. Conclusion: Our analysis demonstrates that it is possible to derive additional information from publicly available expression data using meta-analysis techniques, which is particularly relevant to research into rare diseaseswheresamplenumberscanbelimiting. Keywords: Lupus, Systemic Lupus Erythematosus (SLE), Microarray, Gene expression, Meta-analysis * Correspondence: [email protected] South African National Bioinformatics Institute/Medical Research Council of South Africa Bioinformatics Capacity Development Unit, University of the Western Cape, Cape Town, South Africa © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kröger et al. BMC Medical Genomics (2016) 9:66 Page 2 of 11 Background generally not standardised across studies. The wealth of Systemic Lupus Erythematosus (SLE) is a multi-systemic information contained within these data sets is frequently autoimmune disease associated with high morbidity and underestimated, and often under-utilised once initial ana- mortality. At least nine out of ten lupus patients are female, lyses have been completed. with an onset age of between late teens and early forties. In this study, we have aimed to address some of these There is a significant difference in the prevalence of SLE factors by using an approach that focuses on identifying occurring in different population and ethnic groups, and an mechanistic pathways that may underlie SLE aetiology, occurrence of approximately 40 versus over 200 cases out rather than focusing on the identification of key individ- of 100 000 persons among Northern European or black ual genes. The benefits of addressing differential changes people respectively, has been reported [1, 2]. at a pathway level as opposed to a gene level have previ- There is no predictable course for SLE, and patients ously been described [32, 33]. We have analysed existing can experience alternating periods of disease flare of microarray data sets to identify regulatory networks and varying severity; and remission, during which they have pathways that are dysregulated in SLE, including path- no obvious signs or symptoms. Lupus is also commonly ways that were not identified in the original individual misdiagnosed as it displays a broad range of clinical studies. This is achieved using statistical approaches for presentation resulting from inflammation and damage meta-analysis of the combined results; using data from a caused by the deposition of autoantibody-complexes in variety of microarray expression experiments performed various tissues [3]. There is a wide variety of contribut- using different microarray platforms. We have conducted ing factors attributed to the active disease phenotype the analysis on the premise that not all genes in an and the precise pathological mechanisms of SLE have aetiological pathway will necessarily show high levels of not yet been fully elucidated. Extensive work, however, differential regulation; but that many genes of that path- has shown its aetiology to be multifactorial, with strong way will be differentially regulated to some significant and evidence indicating a substantial genetic component to detectable level. Our approach, therefore, uses less strin- SLE [4–9]. Lupus is now believed to be the result of a gent criteria to select the differentially expressed gene lists complex model in which multiple genes influence the followed by further more stringent pathway analysis. The likelihood of establishing the disease state in response to first statistical approach to select differentially expressed different environmental triggers [10]. The molecular genes is a binning method using quantile discretisation, basis underpinning this disease remains unclear, how- and can analyse microarray datasets from different plat- ever, and more research is required to understand the forms; and the second independent method used to mechanisms contributing to the lupus phenotype. corroborate these results uses a classical scaled approach. The genetic and molecular processes underlying lupus Our analysis demonstrates that it is possible to derive have been extensively investigated using a variety of additional aetiological pathway information from pub- -omics approaches, including genome-wide association licly available expression data, using these meta-analysis studies, candidate gene studies and microarray experi- techniques. This is particularly relevant to research into ments of differential gene expression in lupus samples rare diseases where datasets tend to be fairly small, compared to controls. Many of these data sets are in potentially limiting the statistical significance of findings the public domain, and can be accessed freely by re- from individual studies. Furthermore, this study high- searchers [11–31]. These studies produce extensive and lights the value of sharing datasets in the public domain information-rich data sets that represent a snapshot of once primary analyses are completed. all genetic and/or molecular events occurring in a dis- eased cell at one particular point in time, and can be Methods used to generate hypotheses on the molecular mecha- Inclusion-exclusion criteria for datasets nisms underlying lupus. Microarray studies investigating human peripheral blood The comparison and meta-analysis of such clinical data- mononuclear cells (PBMCs) or any subpopulation thereof sets can be complicated by a variety of factors. Firstly, and (lymphocytes, monocytes or granulocytes) in at least four especially with rare diseases such as SLE, sample size can patients with SLE over the age of 16 were considered. SLE be limiting both in the number of samples included in diagnosis satisfied the criteria set by the American College datasets and the number datasets within the public of Rheumatology [34] or similar. As we were particularly domain. Secondly, because participants in the study are interested in genes differentially expressed during disease usually in clinical care, it is often not possible to stratify flare, lupus patients with disease activity scores of SLE cohorts by treatment regimes, particular clinical symp- Disease Activity Index (SLEDAI; [35, 36]) less than 6, or toms or participant demographics, and matched con- British Isles Lupus Assessment Group (BILAG) C, D or E trols are often not available. Thirdly, the study design, [37, 38] were excluded. Patients on maintenance immuno- participant inclusion criteria and sample type analysed are suppressive treatment but still exhibiting an active disease Kröger et al. BMC Medical Genomics (2016) 9:66 Page 3 of 11 phenotype (SLEDAI ≥ 6and/orBILAGAorB)werein- In the second method a scaling approach was employed. cluded in the study. Samples that were cultured in any We centered and scaled the expression values correspond- way after collection were excluded. Where only subsets of ing to each sample. The result of this operation was to get participants satisfying these criteria were identified, the a mean equal to 0 and a sample standard deviation equal data for these individuals were included in the analysis. to 1 for each sample (across all genes), which tends to can- cel out the inter-sample variations that are non significant
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