Understanding the genetics of systemic lupus erythematosus using Bayesian statistics and gene network analysis.
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ABSTRACT:
SUBMITTER: Nam SW
PROVIDER: S-EPMC8103040 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Systemic lupus erythematosus (SLE) is a chronic, remitting, and relapsing, inflammatory disease involving multiple organs, which exhibits abnormalities of both the innate and adaptive immune responses. A limited number of transcriptomic studies have characterized the gene pathways involved in SLE in an attempt to identify the key pathogenic drivers of the disease. In order to further advance our understanding of the pathogenesis of SLE, we used a novel Bayesian network algorithm to hybridize knowledge- and data-driven methods, and then applied the algorithm to build an SLE gene network using transcriptomic data from 1,760 SLE patients' RNA from the two tabalumab Phase III trials (ILLUMINATE-I & -II), the largest SLE RNA dataset to date. Further, based on the gene network, we carried out hub- and key driver-gene analyses for gene prioritization. Our analyses identified that the JAK-STAT pathway genes, including JAK2, STAT1, and STAT2, played essential roles in SLE pathogenesis, and reaffirmed the recent discovery of pathogenic relevance of JAK-STAT signaling in SLE. Additionally, we showed that other genes, such as IRF1, IRF7, PDIA4, FAM72C, TNFSF10, DHX58, SIGLEC1, and PML, may be also important in SLE and serve as potential therapeutic targets for SLE. In summary, using a hybridized network construction approach, we systematically investigated gene-gene interactions based on their transcriptomic profiles, prioritized genes based on their importance in the network structure, and revealed new insights into SLE activity.
| S-EPMC6886858 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) commonly accredited as "the great imitator" is a highly complex disease involving multiple gene susceptibility with non-specific symptoms. Many experimental and computational approaches have been used to investigate the disease related candidate genes. But the limited knowledge of gene function and disease correlation and also lack of complete functional details about the majority of genes in susceptible locus, encumbrances the identification of SLE related candidate genes. In this paper, we have studied the human immunome network (undirected) using various graph theoretical centrality measures integrated with the gene ontology terms to predict the new candidate genes. As a result, we have identified 8 candidate genes, which may act as potential targets for SLE disease. We have also carried out the same analysis by replacing the human immunome network with human immunome signaling network (directed) and as an outcome we have obtained 5 candidate genes as potential targets for SLE disease. From the comparison study, we have found these two approaches are complementary in nature.
| S-EPMC3847089 | biostudies-literature
Project description:BackgroundA comprehensive intuition of the systemic lupus erythematosus (SLE), as a complex and multifactorial disease, is a biological challenge. Dealing with this challenge needs employing sophisticated bioinformatics algorithms to discover the unknown aspects. This study aimed to underscore key molecular characteristics of SLE pathogenesis, which may serve as effective targets for therapeutic intervention.MethodsIn the present study, the human peripheral blood mononuclear cell (PBMC) microarray datasets (n = 6), generated by three platforms, which included SLE patients (n = 220) and healthy control samples (n = 135) were collected. Across each platform, we integrated the datasets by cross-platform normalization (CPN). Subsequently, through BNrich method, the structures of Bayesian networks (BNs) were extracted from KEGG-indexed SLE, TCR, and BCR signaling pathways; the values of the node (gene) and edge (intergenic relationships) parameters were estimated within each integrated datasets. Parameters with the FDR < 0.05 were considered significant. Finally, a mixture model was performed to decipher the signaling pathway alterations in the SLE patients compared to healthy controls.ResultsIn the SLE signaling pathway, we identified the dysregulation of several nodes involved in the (1) clearance mechanism (SSB, MACROH2A2, TRIM21, H2AX, and C1Q gene family), (2) autoantigen presentation by MHCII (HLA gene family, CD80, IL10, TNF, and CD86), and (3) end-organ damage (FCGR1A, ELANE, and FCGR2A). As a remarkable finding, we demonstrated significant perturbation in CD80 and CD86 to CD28, CD40LG to CD40, C1QA and C1R to C2, and C1S to C4A edges. Moreover, we not only replicated previous studies regarding alterations of subnetworks involved in TCR and BCR signaling pathways (PI3K/AKT, MAPK, VAV gene family, AP-1 transcription factor) but also distinguished several significant edges between genes (PPP3 to NFATC gene families). Our findings unprecedentedly showed that different parameter values assign to the same node based on the pathway topology (the PIK3CB parameter values were 1.7 in TCR vs - 0.5 in BCR signaling pathway).ConclusionsApplying the BNrich as a hybridized network construction method, we highlight under-appreciated systemic alterations of SLE, TCR, and BCR signaling pathways in SLE. Consequently, having such a systems biology approach opens new insights into the context of multifactorial disorders.
| S-EPMC7310461 | biostudies-literature
Project description:Purpose of reviewTo 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 findingsSeveral 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.SummaryKnowledge of the genetics of SLE is advancing rapidly, whereas that of Sjögren's syndrome lags behind considerably.
| S-EPMC8056840 | 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:BackgroundClinical and epidemiological studies have suggested systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are comorbidities and common genetic etiologies can partly explain such coexistence. However, shared genetic determinations underlying the two diseases remain largely unknown.MethodsOur analysis relied on summary statistics available from genome-wide association studies of SLE (N = 23,210) and RA (N = 58,284). We first evaluated the genetic correlation between RA and SLE through the linkage disequilibrium score regression (LDSC). Then, we performed a multiple-tissue eQTL (expression quantitative trait loci) weighted integrative analysis for each of the two diseases and aggregated association evidence across these tissues via the recently proposed harmonic mean P-value (HMP) combination strategy, which can produce a single well-calibrated P-value for correlated test statistics. Afterwards, we conducted the pleiotropy-informed association using conjunction conditional FDR (ccFDR) to identify potential pleiotropic genes associated with both RA and SLE.ResultsWe found there existed a significant positive genetic correlation (r g = 0.404, P = 6.01E-10) via LDSC between RA and SLE. Based on the multiple-tissue eQTL weighted integrative analysis and the HMP combination across various tissues, we discovered 14 potential pleiotropic genes by ccFDR, among which four were likely newly novel genes (i.e., INPP5B, OR5K2, RP11-2C24.5, and CTD-3105H18.4). The SNP effect sizes of these pleiotropic genes were typically positively dependent, with an average correlation of 0.579. Functionally, these genes were implicated in multiple auto-immune relevant pathways such as inositol phosphate metabolic process, membrane and glucagon signaling pathway.ConclusionThis study reveals common genetic components between RA and SLE and provides candidate associated loci for understanding of molecular mechanism underlying the comorbidity of the two diseases.
| S-EPMC8012913 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-06-03 | E-GEOD-46923 | biostudies-arrayexpress
Project description:Genetic studies of systemic lupus erythematosus (SLE) have been successful, identifying numerous risk factors for human disease. While the list is not yet complete, it is clear that important immune system pathways are represented, one of which being type I interferon (IFN). Circulating type I IFN levels are high in SLE patients and this IFN pathway activation is heritable in families with SLE. We summarize our current understanding of the genetics of the type I IFN pathway in SLE, with an emphasis on studies that demonstrate an impact of the SLE-risk alleles upon type I IFN pathway activation in SLE patients. These studies illustrate that variations in type I IFN pathway genes represent a common genetic feature of SLE. By understanding the genetic regulation of type I IFN, we may be able to intervene in a more personalized fashion, based upon the molecular dysregulation present in a given individual.
| S-EPMC3885171 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder. Considerable progress has been made to delineate the genetic control of this complex disorder. In this review, selected aspects of human and mouse genetics related to SLE are reviewed with emphasis on genes that contribute to both innate and adaptive immunity and to genes that contribute directly to susceptibility to end organ damage. It is concluded that the interactions among these two major pathways will provide further insight into the pathogenesis of SLE. An interactive model of the two major pathways is proposed without emphasis on the importance of breaking tolerance to autoantigens.
| S-EPMC4274270 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-06-03 | GSE46923 | GEO