Genetics of systemic lupus erythematosus and Sjogren's syndrome.
Ontology highlight
ABSTRACT: Purpose of review
To determine the advances made in the genetics of systemic lupus erythematosus (SLE) or Sjögren's syndrome as the era of genome-wide association and high-throughput single nucleotide typing begins.Recent findings
Several genome-wide association studies have been performed in SLE but there are no such studies published or in progress for Sjögren's syndrome. Genetics and the functional significance of risk alleles in the interferon pathway are being worked out in detail. This is especially true for STAT4 and IRF5. Gene copy number variation, a major source of genetic variability, is important for several genes that impart risk for SLE. An X chromosome copy number dose effect has recently been identified. Genetic evaluation of Sjögren's syndrome is limited to small studies that have concentrated on genes already shown to be risk factors in SLE.Summary
Knowledge of the genetics of SLE is advancing rapidly, whereas that of Sjögren's syndrome lags behind considerably.
SUBMITTER: Scofield RH
PROVIDER: S-EPMC8056840 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:OBJECTIVE:The diagnosis of SS is often difficult and many patients are symptomatic for years with other diagnoses before confirmation of SS. Our aim was to determine whether overlapping clinical and serologic features with RA and SLE may in part drive the misdiagnoses. METHODS:A total of 1175 sicca patients were evaluated in a multidisciplinary clinic and classified as having SS based on the American-European Consensus Group Criteria. They were interrogated for a past history of suspicion or diagnosis of RA, SLE or SSc. These diseases were confirmed or ruled out by applying the corresponding classification criteria if the patients responded affirmatively. RESULTS:Of these, 524 (44.6%) subjects reported previous diagnosis or suspicion of RA, SLE or SSc, which was confirmed in 130 (24.8%) but excluded in 394 (75.2%) subjects. Of those previously diagnosed with another illness, 183 (34.9%) met the criteria for primary SS. RF was present in 70/191 patients with previous diagnosis of RA compared with 445/845 without a prior RA diagnosis (P = 3.38E-05), while 128/146 with a diagnosis of SLE had positive ANA compared with 622/881 without the diagnosis (P = 8.77E-06). Age also influenced former diagnoses: people with suspected RA were older than those without the diagnosis (P = 5.89E-06), while patients with SLE suspicion were younger (P = 0.0003). Interestingly, the previous diagnoses did not significantly delay a final classification of SS. CONCLUSION:Among subjects classified as SS, the presence of a positive ANA or RF was associated with a previous, apparently erroneous diagnosis of SLE or RA, respectively.
| S-EPMC6281033 | biostudies-other
Project description:Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease which can affect most organ systems including skin, joints and the kidney. Clinically, SLE is a heterogeneous disease and shares features of several other rheumatic diseases, in particular primary Sjögrens syndrome (pSS) and systemic sclerosis (SSc), why it is difficult to diagnose The pathogenesis of SLE is not completely understood, partly due to the heterogeneity of the disease. This study demonstrates that metabolomics can be used as a tool for improved diagnosis of SLE compared to other similar autoimmune diseases. We observed differences in metabolic profiles with a classification specificity above 67% in the comparison of SLE with pSS, SSc and a matched group of healthy individuals. Selected metabolites were also significantly different between studied diseases. Biochemical pathway analysis was conducted to gain understanding of underlying pathways involved in the SLE pathogenesis. We found an increased oxidative activity in SLE, supported by increased xanthine oxidase activity and an increased turnover in the urea cycle. The most discriminatory metabolite observed was tryptophan, with decreased levels in SLE patients compared to control groups. Changes of tryptophan levels were related to changes in the activity of the aromatic amino acid decarboxylase (AADC) and/or to activation of the kynurenine pathway.
| S-EPMC4956266 | biostudies-literature
Project description:PurposeTo describe a triad of fibrous histiocytoma, Systemic Lupus Erythematosus and Sero-positive Sjögren's Syndrome.ObservationsThis case was diagnosed first as bilateral fibrous histiocytoma of cheeks, which on further investigations proved to be a triad of Systemic Lupus Erythematosus, Fibrous histiocytoma and Sero-positive Sjögren's Syndrome.Conclusions and importanceAssociation between fibrous histiocytoma, Systemic Lupus Erythematosus and Sero-positive Sjögren's Syndrome has been known before, but fibrous histiocytoma as first presentation in the triad has not been reported.
| S-EPMC6076362 | biostudies-literature
Project description:BackgroundThe chemokine receptor CCR7 is a key organizer of the immune system. Gene targeting in mice revealed that Ccr7-deficient animals are severely impaired in the induction of central and peripheral tolerance. Due to these defects, Ccr7-deficient mice spontaneously develop multi-organ autoimmunity showing symptoms similar to those observed in humans suffering from connective tissue autoimmune diseases. However, it is unknown whether mutations of CCR7 are linked to autoimmunity in humans.ResultsDNA samples were collected from 160 patients suffering from connective tissue autoimmune disease (Sjogren's syndrome, n = 40; systemic lupus erythematosus, SLE, n = 20 and systemic sclerosis, n = 100) and 40 health subjects (n = 40). All participants in this study were of German descent. Samples were screened for single nucleotide polymorphisms (SNP) by sequencing the coding region of the CCR7 gene as well asthe exon flaking intron sites and parts of the regions encoding for the 5'- and 3'-UTR. CCR7 variants were rare. We identified six different sequence variants, which occurred in heterozygosis. The identified SNP were observed at position -60 C/T (observed 1x), +6,476 A/G (7x), +6,555 C/T (15x), +6,560 C/T (6x), +10,440 A/G (3x) and +11,475 C/A (1x). Four of these variants (+6,476 A/G, +6,555 C/T, +6,560 C/T and +10,440 A/G) display allelic frequencies between 1% and 5 % and were present in both patients and control groups. The variants +6,476 A/G, +6,555 C/T, +6,560 C/T are located in the intron 2, while the +10,440 A/G variant corresponds to a silent mutation in exon 3. The variants -60 C/T and +11,475 C/A which are located at the 5'-UTR and 3-UTR respectively, display allelic frequencies below 1%. No correlation between these variants and the autoimmune diseases investigated could be observed. However, reporter gene expression assay demonstrated that the mutation at the -60 C/T position in homozygosis leads to reduced luciferase activity.ConclusionThese results suggest that variants of CCR7 gene occur at an extremely low frequency in the German population and that neither Sjogren's syndrome, systemic lupus erythematosus, nor systemic sclerosis are associated with these variants. Nevertheless, the decreased luciferase activity observed in cells transfected with the promoter region bearing the -60 C/T mutation suggests that this CCR7 variant could potentially lead to increased susceptibility to autoimmunity.
| S-EPMC1913537 | biostudies-literature
Project description:Objectives: To perform a cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjögren's syndrome (pSS), and healthy controls addressing the question of epigenetic sharing and aiming to detect disease-specific alterations. Methods: DNA extracted from peripheral blood from 347 cases with SLE, 100 cases with pSS, and 400 healthy controls were analyzed on the Human Methylation 450k array, targeting 485,000 CpG sites across the genome. A linear regression model including age, sex, and blood cell type distribution as covariates was fitted, and association p-values were Bonferroni corrected. A random forest machine learning classifier was designed for prediction of disease status based on DNA methylation data. Results: We established a combined set of 4,945 shared differentially methylated CpG sites (DMCs) in SLE and pSS compared to controls. In pSS, hypomethylation at type I interferon induced genes was mainly driven by patients who were positive for Ro/SSA and/or La/SSB autoantibodies. Analysis of differential methylation between SLE and pSS identified 2,244 DMCs with a majority of sites showing decreased methylation in SLE compared to pSS. The random forest classifier demonstrated good performance in discerning between disease status with an area under the curve (AUC) between 0.83 and 0.96. Conclusions: The majority of differential DNA methylation is shared between SLE and pSS, however, important quantitative differences exist. Our data highlight neutrophil dysregulation as a shared mechanism, emphasizing the role of neutrophils in the pathogenesis of systemic autoimmune diseases. The current study provides evidence for genes and molecular pathways driving common and disease-specific pathogenic mechanisms.
| S-EPMC6688520 | biostudies-literature
Project description:ObjectivesRheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share many clinical manifestations and serological features. The aim of this study was to identify the common transcriptional profiling and composition of immune cells in peripheral blood in these autoimmune diseases (ADs).MethodsWe analysed bulk RNA-seq data for enrichment of biological processes, transcription factors (TFs) and deconvolution-based immune cell types from peripheral blood mononuclear cells (PBMCs) in 119 treatment-naive patients (41 RA, 38 pSS, 28 SLE and 12 polyautoimmunity) and 20 healthy controls. The single-cell RNA-seq (scRNA-seq) and flow cytometry had been performed to further define the immune cell subsets on PBMCs.ResultsSimilar transcriptional profiles and common gene expression signatures associated with nucleosome assembly and haemostasis were identified across RA, SLE, pSS and polyautoimmunity. Distinct TF ensembles and gene regulatory network were mainly enriched in haematopoiesis. The upregulated cell-lineage-specific TFs PBX1, GATA1, TAL1 and GFI1B demonstrated a strong gene expression signature of megakaryocyte (MK) expansion. Gene expression-based cell type enrichment revealed elevated MK composition, specifically, CD41b+CD42b+ and CD41b+CD61+ MKs were expanded, further confirmed by flow cytometry in these ADs. In scRNA-seq data, MKs were defined by TFs PBX1/GATA1/TAL1 and pre-T-cell antigen receptor gene, PTCRA. Cellular heterogeneity and a distinct immune subpopulation with functional enrichment of antigen presentation were observed in MKs.ConclusionsThe identification of MK expansion provided new insights into the peripheral immune cell atlas across RA, SLE, pSS and polyautoimmunity. Aberrant regulation of the MK expansion might contribute to the pathogenesis of these ADs.
| S-EPMC8862024 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) and Sjogren's syndrome are chronic inflammatory diseases characterized by the dysfunction of T cells, B cells, and dendritic cells and the production of antinuclear autoantibodies. Here, we evaluate newly discovered molecular and cellular targets for the treatment of SLE and Sjogren's syndrome.The mammalian target of rapamycin in T and B cells has been successfully targeted for treatment of SLE with rapamycin or sirolimus both in patients and animal models. Inhibition of oxidative stress, nitric oxide production, interferon alpha, toll-like receptors 7 and 9, histone deacetylase, spleen tyrosine kinase, proteasome function, lysosome function, endosome recycling, and the nuclear factor kappa B pathway showed efficacy in animal models of lupus. B-cell depletion and blockade of anti-DNA antibodies and T-B cell interaction have shown success in animal models, whereas human studies have so far failed to accomplish clinical endpoints, possibly due to inadequacies in study design.Discovery of novel genes and signaling pathways in lupus pathogenesis offers novel biomarker-targeted approaches for treatment of SLE and Sjogren's syndrome.
| S-EPMC4046639 | biostudies-literature
Project description:ObjectiveTo explore the clinical features of patients with systemic lupus erythematosus and Sjögren's syndrome overlap (SLE-SS) compared to concurrent SLE or primary SS (pSS) patients, we utilized a predictive machine learning-based tool to study SLE-SS.MethodsThis study included SLE, pSS, and SLE-SS patients hospitalized at Nanjing Drum Hospital from December 2018 to December 2020. To compare SLE versus SLE-SS patients, the patients were randomly assigned to discovery cohorts or validation cohorts by a computer program at a ratio of 7:3. To compare SS versus SLE-SS patients, computer programs were used to randomly assign patients to the discovery cohort or the validation cohort at a ratio of 7:3. In the discovery cohort, the best predictive features were determined using a least absolute shrinkage and selection operator (LASSO) logistic regression model among the candidate clinical and laboratory parameters. Based on these factors, the SLE-SS prediction tools were constructed and visualized as a nomogram. The results were validated in a validation cohort, and AUC, calibration plots, and decision curve analysis were used to assess the discrimination, calibration, and clinical utility of the predictive models.ResultsThis study of SLE versus SLE-SS included 290 patients, divided into a discovery cohort (n = 203) and a validation cohort (n = 87). The five best characteristics were selected by LASSO logistic regression in the discovery cohort of SLE versus SLE-SS and were used to construct the predictive tool, including dry mouth, dry eye, anti-Ro52 positive, anti-SSB positive, and RF positive. This study of SS versus SLE-SS included 266 patients, divided into a discovery cohort (n = 187) and a validation cohort (n = 79). In the discovery cohort of SS versus SLE-SS, by using LASSO logistic regression, the eleven best features were selected to build the predictive tool, which included age at diagnosis (years), fever, dry mouth, photosensitivity, skin lesions, arthritis, proteinuria, hematuria, hypoalbuminemia, anti-dsDNA positive, and anti-Sm positive. The prediction model showed good discrimination, good calibration, and fair clinical usefulness in the discovery cohort. The results were validated in a validation cohort of patients.ConclusionThe models are simple and accessible predictors, with good discrimination and calibration, and can be used as a routine tool to screen for SLE-SS.
| S-EPMC9862529 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of antinuclear autoantibodies and the inflammatory infiltration of many organ systems. SLE is a complex disorder in which multiple genetic variants, together with environmental and hormonal factors, contribute to disease risk. In this article, we summarize our current understanding of the genetic contribution to SLE in light of recent genome-wide association studies, which have brought the total number of confirmed SLE susceptibility loci to 29. In the second section, we explore the functional implications of these risk loci and, in particular, highlight the role that many of these genes play in the Toll-like receptor and type I interferon signaling pathways. Finally, we discuss the genetic overlap between SLE and other autoimmune and inflammatory conditions as several risk loci are shared among multiple disorders, suggesting common underlying pathogenic mechanisms.
| S-EPMC2897739 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SjS) are inflammatory systemic autoimmune diseases (SADs) that share several clinical and pathological features. The shared biological mechanisms are not yet fully characterized. The objective of this study was to perform a meta-analysis using publicly available gene expression data about the three diseases to identify shared gene expression signatures and overlapping biological processes.Previously reported gene expression datasets were selected and downloaded from the Gene Expression Omnibus database. Normalization and initial preprocessing were performed using the statistical programming language R and random effects model-based meta-analysis was carried out using INMEX software. Functional analysis of over- and underexpressed genes was done using the GeneCodis tool.The gene expression meta-analysis revealed a SAD signature composed of 371 differentially expressed genes in patients and healthy controls, 187 of which were underexpressed and 184 overexpressed. Many of these genes have previously been reported as significant biomarkers for individual diseases, but others provide new clues to the shared pathological state. Functional analysis showed that overexpressed genes were involved mainly in immune and inflammatory responses, mitotic cell cycles, cytokine-mediated signaling pathways, apoptotic processes, type I interferon-mediated signaling pathways and responses to viruses. Underexpressed genes were involved primarily in inhibition of protein synthesis.We define a common gene expression signature for SLE, RA and SjS. The analysis of this signature revealed relevant biological processes that may play important roles in the shared development of these pathologies.
| S-EPMC4295333 | biostudies-literature