scholarly journals Genomic dissection of Systemic Lupus Erythematosus: Distinct Susceptibility, Activity and Severity Signatures

2018 ◽  
Author(s):  
Nikolaos I. Panousis ◽  
George Bertsias ◽  
Halit Ongen ◽  
Irini Gergianaki ◽  
Maria Tektonidou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Whole Blood ◽  
Personalized Therapy ◽  
Flare Activity ◽  
Rna Seq ◽  
Healthy Individuals ◽  
Systemic Lupus

AbstractRecent genetic and genomics approaches have yielded novel insights in the pathogenesis of Systemic Lupus Erythematosus (SLE) but the diagnosis, monitoring and treatment still remain largely empirical1,2. We reasoned that molecular characterization of SLE by whole blood transcriptomics may facilitate early diagnosis and personalized therapy. To this end, we analyzed genotypes and RNA-seq in 142 patients and 58 matched healthy individuals to define the global transcriptional signature of SLE. By controlling for the estimated proportions of circulating immune cell types, we show that the Interferon (IFN) and p53 pathways are robustly expressed. We also report cell-specific, disease-dependent regulation of gene expression and define a core/susceptibility and a flare/activity disease expression signature, with oxidative phosphorylation, ribosome regulation and cell cycle pathways being enriched in lupus flares. Using these data, we define a novel index of disease activity/severity by combining the validated Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)1 with a new variable derived from principal component analysis (PCA) of RNA-seq data. We also delineate unique signatures across disease endo-phenotypes whereby active nephritis exhibits the most extensive changes in transcriptome, including prominent drugable signatures such as granulocyte and plasmablast/plasma cell activation. The substantial differences in gene expression between SLE and healthy individuals enables the classification of disease versus healthy status with median sensitivity and specificity of 83% and 100%, respectively. We explored the genetic regulation of blood transcriptome in SLE and found 3142 cis-expression quantitative trait loci (eQTLs). By integration of SLE genome-wide association study (GWAS) signals and eQTLs from 44 tissues from the Genotype-Tissue Expression (GTEx) consortium, we demonstrate that the genetic causality of SLE arises from multiple tissues with the top causal tissue being the liver, followed by brain basal ganglia, adrenal gland and whole blood. Collectively, our study defines distinct susceptibility and activity/severity signatures in SLE that may facilitate diagnosis, monitoring, and personalized therapy.

scholarly journals Machine learning applied to whole-blood RNA-sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus

2019 ◽  
Author(s):  
William A Figgett ◽  
Katherine Monaghan ◽  
Milica Ng ◽  
Monther Alhamdoosh ◽  
Eugene Maraskovsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Systemic Lupus Erythematosus ◽  
Clinical Trials ◽  
Lupus Erythematosus ◽  
Whole Blood ◽  
Rna Seq ◽  
Systemic Lupus ◽  
Disease Heterogeneity ◽  
Healthy Donors

ABSTRACTObjectiveSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the whole-blood transcriptomes of patients with SLE.MethodsWe applied machine learning approaches to RNA-sequencing (RNA-seq) datasets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta-analysis on two recently published whole-blood RNA-seq datasets was carried out and an additional similar dataset of 30 patients with SLE and 29 healthy donors was contributed in this research; 141 patients with SLE and 51 healthy donors were analysed in total.ResultsExamination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease-related genes relative to clinical presentation. Moreover, gene signatures correlated to flare activity were successfully identified.ConclusionGiven that disease heterogeneity has confounded research studies and clinical trials, our approach addresses current unmet medical needs and provides a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy to harness disease heterogeneity and identify patient populations that may be at an increased risk of disease symptoms. Further, this approach can be used to understand the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy.

scholarly journals Polymorphisms of MFGE8 are associated with susceptibility and clinical manifestations through gene expression modulation in Koreans with systemic lupus erythematosus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wook-Young Baek ◽  
Ji-Min Woo ◽  
Hyoun-Ah Kim ◽  
Ju-Yang Jung ◽  
Chang-Hee Suh
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Milk Fat ◽  
Clinical Manifestations ◽  
Αvβ3 Integrin ◽  
Apoptotic Cells ◽  
Systemic Lupus ◽  
Dsdna Antibody

AbstractSystemic lupus erythematosus (SLE) is characterized by impaired clearance of apoptotic cells. Milk fat globule epidermal growth factor 8 (MFGE8) is a protein that connects αvβ3 integrin on phagocytic macrophages with phosphatidylserine on apoptotic cells. We investigated whether genetic variation of the MFGE8 gene and serum MFGE8 concentration are associated with SLE. Single nucleotide polymorphisms (SNPs) were genotyped and serum concentrations were analyzed. The rs2271715 C allele and rs3743388 G allele showed higher frequency in SLE than in healthy subjects (HSs). Three haplotypes were found among 4 SNPs (rs4945, rs1878327, rs2271715, and rs3743388): AACG, CGCG, and CGTC. CGCG haplotype was significantly more common in SLE than in HSs. rs4945 was associated with the erythrocyte sedimentation rate and rs1878327 was associated with alopecia, C-reactive protein, complement 3, anti-dsDNA antibody, and high disease activity. rs2271715 and rs3743388 were associated with renal disease, cumulative glucocorticoid dose, and cyclophosphamide and mycophenolate mofetil use. Serum MFGE8 concentrations were significantly higher in SLE than in HSs. Furthermore, the levels of MFGE8 were significantly higher in SLE than HSs of the rs2271715 CC genotype. In conclusion, MFGE8 genetic polymorphisms are associated not only with susceptibility to SLE but also with disease activity through modulation of gene expression.

scholarly journals Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

2020 ◽  
Author(s):  
Vasilis F. Ntasis ◽  
Nikolaos I. Panousis ◽  
Maria G. Tektonidou ◽  
Emmanouil T. Dermitzakis ◽  
Dimitrios T. Boumpas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Gene Expression Data ◽  
Lupus Erythematosus ◽  
Genome Organization ◽  
Expression Data ◽  
Systemic Lupus ◽  
Gene Coexpression ◽  
Kidney Involvement

AbstractSystemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. We developed a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). By implementing this method on gene expression data from a large SLE patient cohort, we identify significant disease-associated alterations in gene co-regulation patterns, which also correlate with the SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to DCEs of smaller size. High disease activity genomes display excessive spatial redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. Fragmentation and redistribution of gene coexpression patterns correlate with SLE-implicated biological pathways and clinically relevant endophenotypes such as kidney involvement. Notably, genes lying at the boundaries of split DCEs of low activity genomes are enriched in the interferon and other SLE susceptibility signatures, suggesting the implication of DCE fragmentation at early disease stages. Interrogation of promoter-enhancer interactions from various immune cell subtypes shows that a significant percentage of nested connections are disrupted by a DCE split or depletion in SLE genomes. Collectively, our results underlining an important role for genome organization in shaping gene expression in SLE, could provide valuable insights into disease pathogenesis and the mechanisms underlying disease flares.SignificanceAlthough widespread gene expression changes have been reported in Systemic Lupus Erythematosus (SLE), attempts to link gene deregulation with genome structure have been lacking. Through a computational framework for the segmentation of gene expression data, we reveal extensive fragmentation and reorganization of gene co-regulation domains in SLE, that correlates with disease activity states. Gene co-expression domains pertaining to biological functions implicated in SLE such as the interferon pathway, are being disrupted in patients, while others associated to severe manifestations such as nephritis, emerge in previously uncorrelated regions of the genome. Our results support extensive genome re-organization underlying aberrant gene expression in SLE, which could assist in the early detection of disease flares in patients that are in remission.Graphical Abstract

scholarly journals A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus

2014 ◽  
Vol 150 (2) ◽  
pp. 192-200 ◽  
Author(s):  
Alexandros P. Grammatikos ◽  
Vasileios C. Kyttaris ◽  
Katalin Kis-Toth ◽  
Lisa M. Fitzgerald ◽  
Amy Devlin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
T Cell ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Cell Gene Expression ◽  
Cell Gene

Fyn and CD70 Expression in CD4+ T Cells from Patients with Systemic Lupus Erythematosus

2009 ◽  
Vol 37 (1) ◽  
pp. 53-59 ◽  
Author(s):  
ANNA KOZLOWSKA ◽  
PAWEL HRYCAJ ◽  
JAN K. LACKI ◽  
PAWEL P. JAGODZINSKI
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Disease Activity ◽  
Protein Content ◽  
Lupus Erythematosus ◽  
Cd4 T Cells ◽  
Healthy Individuals ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Protein Levels

Objective.CD4+ T cells from patients with systemic lupus erythematosus (SLE) display defective function that contributes to abnormal activation of B cells and autoantibody production.Methods.We compared the transcript and protein levels of Fyn and CD70 in CD4+ T cells from patients with SLE (n = 41) and healthy individuals (n = 34). The CD4+ T cells were isolated by positive biomagnetic separation technique. The quantitative analysis of messenger RNA was performed by reverse transcription and real-time quantitative PCR. The protein contents in the CD4+ T cells were determined by Western blotting analysis.Results.We observed significantly higher levels of Fyn (p = 0.03) and CD70 (p = 0.029) transcripts in SLE CD4+ T cells than in controls. There was a significant increase in CD70 protein levels (p < 0.0001), but not Fyn protein levels (p = 0.081) in CD4+ T cells from patients with SLE compared to healthy individuals. In the group with high disease activity [SLE Disease Activity Index (SLEDAI) ≥ 9], we observed a significantly higher Fyn protein content than in controls (p = 0.030). There was no correlation between Fyn and CD70 protein levels in SLE CD4+ T cells and disease activity as expressed in the SLEDAI scale.Conclusion.We confirmed previous observations of higher expression of CD70 in CD4+ T cells from patients with SLE. Our findings suggest that increased Fyn protein content in CD4+ T cells can be associated with high SLE disease activity.

scholarly journals Stratification of Systemic Lupus Erythematosus Patients Into Three Groups of Disease Activity Progression According to Longitudinal Gene Expression

2018 ◽  
Vol 70 (12) ◽  
pp. 2025-2035 ◽  
Author(s):  
Daniel Toro‐Domínguez ◽  
Jordi Martorell‐Marugán ◽  
Daniel Goldman ◽  
Michelle Petri ◽  
Pedro Carmona‐Sáez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Systemic Lupus

Circular RNAS: novel biomarkers of disease activity in systemic lupus erythematosus?

2019 ◽  
Vol 133 (9) ◽  
pp. 1049-1052 ◽  
Author(s):  
Raquel Cortes ◽  
Maria J. Forner
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Circular Rnas ◽  
Systemic Lupus ◽  
Competitive Endogenous Rnas ◽  
Potential Biomarker ◽  
Inflammatory Processes

Abstract Circular RNAs (circRNAs) are a class of non-coding RNAs that regulate gene expression by acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Several studies support the implication of circRNAs in a variety of human diseases, but research on the role of circRNAs in systemic lupus erythematosus (SLE) is lacking. In a study recently published in Clinical Science (2018), Zhang et al. identified hsa_circ_0012919 as a potential biomarker of disease activity in SLE patients. The authors observed different circRNA expression between SLE patients and healthy controls, an association with clinical variables and with the abnormal DNA methylation present in SLE CD4+ T cells. Finally, Zhang et al. demonstrated that hsa_circ_0012919 acts as a miRNA sponge for miR-125a-3p, regulating the gene expression of targets RANTES and KLF13 that are involved in the physiology and pathophysiology of acute and chronic inflammatory processes. These findings support the role of circRNAs in the pathophysiology of SLE.

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