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Extensive Changes in Transcription Dynamics Reflected on Alternative Splicing Events in Systemic Lupus Erythematosus Patients.

ABSTRACT: In addition to increasing the complexity of the transcriptional output, alternative RNA splicing can lead to the reduction of mRNA translation or the production of non-functional or malfunctional proteins, thus representing a vital component of the gene regulation process. Herein, we set out to detect and characterize alternative splicing events that occur in whole-blood samples of patients with Systemic Lupus Erythematosus (SLE) as compared to healthy counterparts. Through the implementation of a computational pipeline on published RNA-sequencing data, we identified extensive changes in the transcription dynamics affecting a large number of genes. We found a predominance of intron retention events, with the majority introducing premature stop codons, suggestive of gene repression, in both inactive and active SLE patient samples. Alternative splicing affected a distinct set of genes from the ones detected as differentially expressed in the same comparisons, while alternatively spliced genes tended to reside in genome areas associated with increased gene co-expression. Functional analysis of genes affected by alternative splicing pointed towards particular functions related to metabolism and histone acetylation as of potential interest. Together, our findings underline the importance of incorporating alternative splicing analyses in the context of molecular characterization of complex diseases such as SLE.

SUBMITTER: Papanikolaou S

PROVIDER: S-EPMC8392844 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Extensive fragmentation and re-organization of transcription in Systemic Lupus Erythematosus.

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Project description:Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE. In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples. TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets-one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE. These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-03 | E-GEOD-46923 | biostudies-arrayexpress

Systemic Lupus Erythematosus with Multiple Autoimmune Disease Presented with Extensive Peripheral Gangrene.

Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease and can be associated with other autoimmune diseases. SLE usually presents with skin change and rarely presents with gangrene. SLE gangrene usually involves the digits of upper extremities. We report the first case of SLE associated with an extremely rare constellation of neuromyelitis Optica (NMO) and diabetes mellitus type 1, presented with a rare form of the SLE gangrene which involves bilateral lower extremities up to midlegs, a case that has not yet been reported in the literature. Although SLE gangrene may respond to immunosuppressants, it has a high risk of complications that can end up with amputations.

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Project description:This SuperSeries is composed of the SubSeries listed below.

2014-06-03 | GSE46923 | GEO

Systemic lupus erythematosus.

Project description: Not available

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Systemic lupus erythematosus.

Project description: Not available

| S-EPMC2048842 | biostudies-literature

Race/Ethnicity and Cardiovascular Events Among Patients With Systemic Lupus Erythematosus.

Project description:OBJECTIVE:Systemic lupus erythematosus (SLE) is more prevalent and results in more severe outcomes among blacks, Asians, and Hispanics than among whites. Cardiovascular disease (CVD) is the leading cause of death among SLE patients. We undertook this study to examine racial/ethnic variations in risk of CVD events among SLE patients. METHODS:Within the Medicaid Analytic eXtract from 2000 to 2010, we identified patients ages 18-65 years with SLE (?3 International Classification of Diseases, Ninth Revision 710.0 codes, ?30 days apart) and with ?12 months of continuous enrollment. Subjects were followed up from the index date to the first CVD event (myocardial infarction [MI] or stroke), death, disenrollment, loss to follow-up, or end of follow-up period. Race/ethnicity-specific annual CVD event rates were calculated. Cox regression models estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs), accounting for competing risk of death and adjusting for baseline demographics and comorbidities. RESULTS:Of 65,788 SLE patients, 93.1% were women and ?42% were black, 38% were white, 16% were Hispanic, 3% were Asian, and 1% were American Indian/Alaska Native. Mean?±?SD follow-up was 3.8?±?3.1 years. CVD event rates were highest among blacks (incidence rate [IR] 10.57 [95% CI 9.96-11.22]) and lowest among Asians (IR 6.63 [95% CI 4.97-8.85]). After multivariable adjustment, risk of CVD events was increased among blacks (HR 1.14 [95% CI 1.03-1.26]) compared to whites. Hispanics and Asians had a lower risk of MI (HR 0.61 [95% CI 0.48-0.77] and HR 0.57 [95% CI 0.34-0.96], respectively), while blacks and Hispanics had a higher risk of stroke (HR 1.31 [95% CI 1.15-1.49] and HR 1.22 [95% CI 1.03-1.44], respectively). CONCLUSION:Among SLE patients enrolled in Medicaid, the risk of MI was lower among Hispanics and Asians compared to whites, while the risk of stroke was elevated among blacks and Hispanics compared to whites.

| S-EPMC6143392 | biostudies-literature

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