Dataset Information

Exploring the causality and pathogenesis of systemic lupus erythematosus in breast cancer based on Mendelian randomization and transcriptome data analyses.

ABSTRACT:

Introduction

There has been a cumulative interest in relationships between systemic lupus erythematosus (SLE) and cancer risk. Breast cancer is the most common cancer among women worldwide. However, the casual association and pathogenesis between SLE and breast cancer remains incompletely unknown.

Methods

Mendelian randomization (MR) analysis was first conducted to investigate the potential causality between SLE and breast cancer. Sensitivity analyses were applied to validate the reliability of MR results. Transcriptomic data analyses based on the Cancer Genome Atlas and Gene Expression Omnibus databases were then performed to identify and construct a SLE-related gene signature (SLEscore).

Results

The MR analysis demonstrated that genetic predisposition to SLE was casually associated with the decreased risk of breast cancer in the East Asian cohort (odds ratios: 0.95, 95% confidence interval: 0.92-0.98, p=0.006). However, no casual associations were observed in the European population. Furthermore, sensitivity analyses proved the robustness of the present MR results. A prognostic SLEscore consisting of five SLE-related genes (RACGAP1, HMMR, TTK, TOP2A, and KIF15) could distribute patients with breast cancer into the high- and low-risk groups according to survival rates with good predictive ability (p < 0.05).

Conclusion

Our MR study provided evidence that genetic changes in SLE were significantly associated with the decreased risk of breast cancer in the East Asian population, while no causality was found in the European cohorts. Transcriptome data analyses indicated that the SLEscore could serve as a novel biomarker for predicting prognosis when breast cancer and SLE coexisted in patients.

SUBMITTER: Li W

PROVIDER: S-EPMC9885086 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Exploring the causality and pathogenesis of systemic lupus erythematosus in breast cancer based on Mendelian randomization and transcriptome data analyses.

Li Wenjie W Wang Rong R Wang Wei W

Frontiers in immunology 20230116

<h4>Introduction</h4>There has been a cumulative interest in relationships between systemic lupus erythematosus (SLE) and cancer risk. Breast cancer is the most common cancer among women worldwide. However, the casual association and pathogenesis between SLE and breast cancer remains incompletely unknown.<h4>Methods</h4>Mendelian randomization (MR) analysis was first conducted to investigate the potential causality between SLE and breast cancer. Sensitivity analyses were applied to validate the ...[more]

PMID: 36726984

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Project description:ObjectiveNumerous observational studies have found a relationship between systemic lupus erythematosus (SLE) and epilepsy; however, their causal relationship remains unclear. This study aimed to investigate the causal role of SLE in epilepsy or any of its subtypes using a two-sample Mendelian randomization (MR) analysis.MethodsSingle nucleotide polymorphisms (SNPs) linked to SLE were utilized as instrumental variables in MR analysis to assess their causal impact on epilepsy. The primary MR findings were derived using the inverse variance weighted (IVW) method, which was further supported by the weighted median and MR-Egger regression techniques. Additionally, sensitivity analyses, including Cochran's Q test and pleiotropy tests, were conducted to evaluate the influence of these SNPs on epilepsy, particularly looking for signs of horizontal pleiotropy and heterogeneity.ResultsWe selected 43 SNPs that reached genome-wide significance from genome-wide association studies (GWASs) on SLE to serve as instrumental variables in this study. The IVW method showed no evidence to support a causal association between SLE and epilepsy (all epilepsy: odds ratio (OR) = 1.006, 95% confidence interval (CI) = 0.994-1.018; focal epilepsy: OR = 1.006, 95% CI = 0.994-1.019; generalized epilepsy: OR = 1.015, 95% CI = 0.996-1.035). Other MR complementary methods revealed consistent results. Furthermore, there was no evidence indicating heterogeneity or horizontal pleiotropy.SignificanceThe findings of MR analysis did not support a genetically predicted causal relationship between SLE and epilepsy, but emphasized the need for further research on shared pathophysiological mechanisms, particularly the role of immune system abnormalities and potential influences such as chronic inflammation and therapeutic interventions.Plain language summaryThe etiology of epilepsy is complex and diverse, including immune factors. Through a Mendelian randomization analysis, we did not find evidence of a genetic causal relationship between systemic lupus erythematosus and epilepsy. However, this does not invalidate epidemiological evidence, and further exploration is needed to investigate factors influencing the relationship between the two.

Project description:BackgroundAccumulating evidence supports the predisposition of systemic lupus erythematosus (SLE) to atherosclerosis (AS). However, the common pathogenesis of these two diseases remains unclear. This study aimed to explore the mechanisms of SLE complicated by AS.MethodsGene expression profiles of SLE (GSE50772) and AS (GSE100927) were downloaded from the Gene Expression Omnibus. We analyzed differentially expressed genes (DEGs) of SLE and AS and performed enrichment analyses separately. After analyzing the common DEGs (CDEGs), we performed functional enrichment analysis, protein-protein interaction (PPI) network analysis, and hub genes (HGs) identification of CDEGs. Then, we performed a co-expression analysis of HGs and verified their expression and diagnostic value. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells (IICs). Finally, we verified the reliability of the screening pathway.ResultsWe obtained 530 DEGs from the GSE50772 dataset and 448 DEGs from the GSE100927 dataset. The results of the enrichment analysis showed that there were many similar immune- and inflammation-related processes between the two diseases. We analyzed 26 CDEGs (two downregulated genes and 24 upregulated genes) and enrichment analysis highlighted the important role of the IL-17 signaling pathway. We identified five HGs (CCR1, CD163, IL1RN, MMP9, and SIGLEC1) using the CytoHubba plugin and HGs validation showed that the five HGs screened were reliable. Co-expression networks showed that five HGs can affect mononuclear cell migration. Immune cell infiltration analysis indicated monocytes in SLE and M0 macrophages in AS accounted for a high proportion of all IICs, and the difference in infiltration was obvious. We also found a significant positive correlation between CCR1, CD163, IL1RN, and MMP9 and monocytes in SLE, and a significant positive correlation between CCR1, IL1RN, MMP9, and SIGLEC1 and M0 macrophages in AS. Pathway validation also demonstrated that the IL-17 signaling pathway was a key pathway for the differentiation of monocytes into macrophages.ConclusionsThe five HGs may promote the differentiation of monocytes into macrophages by influencing the IL-17 signaling pathway, leading to SLE complicated by AS. Our study provides insights into the mechanisms of SLE complicated by AS.

Dataset Information

Exploring the causality and pathogenesis of systemic lupus erythematosus in breast cancer based on Mendelian randomization and transcriptome data analyses.

Introduction

Methods

Results

Conclusion

Publications

Exploring the causality and pathogenesis of systemic lupus erythematosus in breast cancer based on Mendelian randomization and transcriptome data analyses.

Similar Datasets

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