Abstract The genome-wide association study is a free-hypothesis approach based on screening of thousands or even millions of genetic variants distributed throughout the whole human genome in relation ...to a phenotype. The relevant role of the genome-wide association studies in the last decade is undisputed because it has permitted to elucidate multiple risk genetic factors associated with the susceptibility to several human complex diseases. Regarding systemic lupus erythematosus (SLE) this approach has allowed to identify more than 60 risk loci for SLE susceptibility across populations to date, increasing our understanding on the pathogenesis of this disease. We present the latest findings in the genetic of SLE across populations using genome-wide approaches. These studies revealed that most of the genetic risk is shared across borders and ethnicities. Finally, we focus on describing the most important risk loci for SLE attempting to cover the genetic findings in relation to functional polymorphisms, such as missense single nucleotide polymorphisms (SNPs) or regulatory variants involved in the development of the disease. The functional studies try to identify the causality of some GWAS-associated variants, many of which fall in non-coding regions of the genome, suggesting a regulatory role. Many loci show an environmental interaction, another aspect revealed by the studies of epigenetic modifications and those associated with genetic variants. Finally, new-generation sequencing technologies can open other paths in the research on SLE genetics, the role of rare variants and the detailed identification of causal regulatory variation. The clinical relevance of the genetic factors will be shown when we are able to use them or in combination with other molecular measurements to re-classify a heterogeneous disease such as SLE.
Objective
Anti‐Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (SS), systemic lupus ...erythematosus (SLE), and undifferentiated connective tissue disease (UCTD). This study was undertaken to determine if there is a common signature for all patients expressing anti–Ro 60 autoantibodies regardless of their disease phenotype.
Methods
Using high‐throughput multiomics data collected from the cross‐sectional cohort in the PRECISE Systemic Autoimmune Diseases (PRECISESADS) study Innovative Medicines Initiative (IMI) project (genetic, epigenomic, and transcriptomic data, combined with flow cytometry data, multiplexed cytokines, classic serology, and clinical data), we used machine learning to assess the integrated molecular profiling of 520 anti–Ro 60+ patients compared to 511 anti–Ro 60– patients with primary SS, patients with SLE, and patients with UCTD, and 279 healthy controls.
Results
The selected clinical features for RNA‐Seq, DNA methylation, and genome‐wide association study data allowed for a clear distinction between anti–Ro 60+ and anti–Ro 60– patients. The different features selected using machine learning from the anti–Ro 60+ patients constituted specific signatures when compared to anti–Ro 60– patients and healthy controls. Remarkably, the transcript Z score of 3 genes (ATP10A, MX1, and PARP14), presenting with overexpression associated with hypomethylation and genetic variation and independently identified using the Boruta algorithm, was clearly higher in anti–Ro 60+ patients compared to anti–Ro 60– patients regardless of disease type. Our findings demonstrated that these signatures, enriched in interferon‐stimulated genes, were also found in anti–Ro 60+ patients with rheumatoid arthritis and those with systemic sclerosis and remained stable over time and were not affected by treatment.
Conclusion
Anti–Ro 60+ patients present with a specific inflammatory signature regardless of their disease type, suggesting that a dual therapeutic approach targeting both Ro‐associated RNAs and anti–Ro 60 autoantibodies should be considered.
Objective
To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, ...52‐week, randomized, placebo‐controlled, double‐blind studies in which patients were treated with the BAFF‐blocking IgG4 monoclonal antibody tabalumab.
Methods
Patient samples were obtained from SLE patients from the ILLUMINATE‐1 and ILLUMINATE‐2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString.
Results
At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti–double‐stranded DNA (anti‐dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell–related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti‐dsDNA antibody, C3, and immunoglobulin levels.
Conclusion
SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE‐1 and ILLUMINATE‐2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
Abstract Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease, have complex pathogeneses and likely multifactorial ...etiologies. The current paradigm for understanding their development is that the disease is triggered in genetically-susceptible individuals by exposure to environmental factors. Some of these environmental factors have been specifically identified, while others are hypothesized and not yet proven, and it is likely that most have yet to be identified. One interesting hypothesis is that environmental effects on immune responses could be mediated by changes in epigenetic regulation. Major mechanisms of epigenetic gene regulation include DNA methylation and histone modification. In these cases, gene expression is modified without involving changes in DNA sequence. Epigenetics is a new and interesting research field in autoimmune diseases. We review the roles of genetic factors, epigenetic regulation and the most studied environmental risk factors such as cigarette smoke, crystalline silica, Epstein–Barr virus, and reproductive hormones in the pathogenesis of autoimmune disease.
The B cell adaptor protein with ankyrin repeats (BANK1) and the B lymphoid tyrosine kinase (BLK) have been genetically associated with autoimmunity. The proteins of these genes interact physically ...and work in concert during B-cell signaling. Little is know about their interactions with other B-cell signaling molecules or their role in the process. Using yeast two hybrid (Y2H) we sought for factors that interact with BANK1. We found that the molecular switch PLCg2 interacts with BANK1 and that the interaction is promoted by B-cell receptor (BCR) stimulation. We found further that the kinase activity of BLK enhanced BANK1- PLCg2 binding and that the interaction was suppressed upon BLK depletion. Immunoprecipitation and mutational analysis demonstrated that the interaction between BANK1 and PLCg2 was dependent on specific tyrosine and proline residues on the adaptor protein. Our results provide new information important to understand the role of these two genes in basic B-cell physiology and immune-related diseases.
The purpose of our study was to investigate the effects of the adaptor Bank1 in TLR7 signaling using the B6.Sle1.yaa mouse, a lupus model that develops disease through exacerbated TLR7 expression. ...Crosses of B6.Sle1.yaa with Bank1-/- mice maintained several B and myeloid cell phenotypes close to normal wild-type levels. Most striking was the reduction in total serum IgG antibodies, but not of IgM, and reduced serum levels of autoantibodies, IL-6, and BAFF. Bank1 deficiency did modify numbers of MZ B cells and total B cell numbers, as well as expression of CXCR4 by follicular helper T cells. Other T cell changes were not observed. Bank1 deficiency did not modify numbers of germinal center B cells or plasma cells or clinical disease outcomes. Purified B cells from Bank1 deficient mice had strongly reduced Ifnb, Ifna4, Irf7, Aicda and Stat1 gene expression following TLR7 agonist stimulation. Interestingly, phosphorylation of Tyr701, but not of Ser727 of STAT1, was impaired in splenic B cells from B6.Sle1.yaa.Bank1-/- mice, as was the nuclear translocation of IRF7 in response to TLR7 agonist stimulation. Further, Bank1 deficiency in B6.Sle1.yaa mice reduced the production of IgG2c after in vitro TLR7 agonist stimulation. Our results demonstrate that Bank1 controls TLR7-mediated type I interferon production. Combined with the control of the nuclear translocation of IRF7, the modulation of STAT1 transcription and phosphorylation, Bank1 contributes to IgG production during development of autoimmune disease.
•Metabolic differences in Systemic Sclerosis were found in plasma and urine samples.•The main deregulated metabolites were acylcarnitines, acylglycines and aminoacids.•The main plasma biomarker ...candidate was 2-arachidonoylglycerol.•Larger differences were found in urine samples than in plasma.•Results indicate perturbations in fatty acid beta oxidation and aminoacid pathways.
Systemic Sclerosis (SSc) is a chronic autoimmune disease whose origin and pathogenesis are not yet well known. Recent studies are allowing a better definition of the disease. However, few studies have been performed based on metabolomics. In this way, this study aims to find altered metabolites in SSc patients in order to improve their diagnosis, prognosis and treatment. For that, 59 SSc patients and 28 healthy volunteers participated in this study. Urine and plasma samples were analysed by a fingerprinting metabolomic approach based on HPLC-ESI-QTOF-MS. We observed larger differences in urine than plasma metabolites. The main deregulated metabolic families in urine were acylcarnitines, acylglycines and metabolites derived from amino acids, specifically from proline, histidine and glutamine. These results indicate perturbations in fatty acid beta oxidation and amino acid pathways in scleroderma patients. On the other hand, the main plasma biomarker candidate was 2-arachidonoylglycerol, which is involved in the endocannabinoid system with potential implications in the induction and propagation of systemic sclerosis and autoimmunity.
Much is said about precision medicine, but its real significance and potential are far from certain. Several studies in each of the autoimmune diseases have provided important insights into molecular ...pathways, but the use of molecular studies, particularly those looking into transcriptome pathways, has seldom approached the possibility of using the data for disease stratification and then for prediction, or for diagnosis. Only the type I IFN signature has been considered for therapeutic purposes, particularly in the case of SLE. This review provides an update on precision medicine, on what can be translated into clinical practice and on what single-cell molecular studies contribute to our knowledge of autoimmune diseases, focusing on a few examples. The main message is that we should try to move from precision medicine of established diseases to preventive medicine in order to predict the development of disease.
To describe the recent studies on the genetics of systemic lupus erythematosus (SLE) and Sjögren's syndrome.
We overview the most recent findings on the genetic susceptibility of the diseases and ...provide information on their genetic similarities and differences.
SLE and Sjögren's syndrome are two closely related systemic autoimmune diseases that share multiple clinical and molecular aspects, including a significant number of susceptibility genes. Several genome-wide association studies were recently published in different populations that provide a better picture of their molecular mechanisms. It is becoming clear that their genetic architecture is quite well established, but more information is required on expression quantitative trait loci, epigenetic genome-wide analyses, gene × gene interactions and the role of rare variants.
Abstract
Summary
The Gene Expression Omnibus (GEO) database provides an invaluable resource of publicly available gene expression data that can be integrated and analyzed to derive new hypothesis and ...knowledge. In this context, gene expression meta-analysis (geMAs) is increasingly used in several fields to improve study reproducibility and discovering robust biomarkers. Nevertheless, integrating data is not straightforward without bioinformatics expertise. Here, we present ImaGEO, a web tool for geMAs that implements a complete and comprehensive meta-analysis workflow starting from GEO dataset identifiers. The application integrates GEO datasets, applies different meta-analysis techniques and provides functional analysis results in an easy-to-use environment. ImaGEO is a powerful and useful resource that allows researchers to integrate and perform meta-analysis of GEO datasets to lead robust findings for biomarker discovery studies.
Availability and implementation
ImaGEO is accessible at http://bioinfo.genyo.es/imageo/.
Supplementary information
Supplementary data are available at Bioinformatics online.
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