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Background: Patients with Systemic Lupus Erythematosus (SLE) are at a higher risk of suffering major cardiovascular events due to accelerated atherosclerosis. Their occurrence is not explained by traditional risk factors [1], suggesting SLE-specific immune processes such as aberrant immunological activation and endothelial cell dysfunction [2]. We analyzed a transcriptomic dataset of patients with demonstrated atherosclerosis to identify enriched genes related to coronary atherosclerosis.
Objectives: To identify enriched genes and cellular infiltration patterns in peripheral blood samples of coronary artery disease in patients with Lupus.
Methods: The dataset GSE154851 was downloaded and analyzed with the Gene Set Enrichment Analysis (GSEA) platform to identify genes enriched in the process of coronary artery atherosclerosis. Patients from this dataset met the 1997 American College of Rheumatology (ACR) and 2012 Systemic Lupus International Collaboration Clinics criteria (SLICC). Protein-protein interactions (PPIs) were constructed using Cytospace, and hub genes were identified with the Cytohubba plugin. Cellular infiltration populations were analyzed using Cibersort, and results were compared with dataset GSE110174. Patients from this dataset were classified according to the British Isles Lupus Assessment Group (BILAG). All utilized software is free-access and available to the public. Significant differences in cellular populations between groups were identified using one way ANOVA test and Bonferroni post hoc analysis.
Results: 18 genes were enriched for coronary artery atherosclerosis. MYLK, ACTA2, SMAD3, MYH11, TGFBR1, PPARG, ABCA1, CYP7A1, PCSK9, and APOB were identified as hub genes of coronary atherosclerosis (Figure 1).Digital cytometry analysis (Table 1) resulted in significant differences in CD8+ T Cells (SLEAt vs. SLE p = 0.001 ), CD4+ Naïve T Cells (SLEAt vs. SLE p < 0.001 , SLE vs. HC p < 0.001 ), CD4+ Resting Memory T Cells (SLEAt vs. SLE p < 0.001 , SLEAt vs. HC p < 0.001 , SLE vs. HC p < 0.001 ), CD4+ Activated Memory T Cells (SLEAt vs. SLE p < 0.001 , SLE vs. HC p < 0.001 ), Regulatory T Cells (SLEAt vs. SLE p = 0.012 , SLE vs. HC p = 0.017 ), Resting NK Cells (SLEAt vs. SLE p < 0.001 , SLEAt vs. HC p = 0.003 , SLE vs. HC p < 0.001 ), Activated NK Cells (SLE vs. HC p < 0.001 ) Monocytes (SLEAt vs. SLE p < 0.001 , SLEAt vs. HC p = 0.001 , SLE vs. HC p < 0.001 ), and Neutrophils (SLEAt vs. HC p = 0.016 ).
Hub genes of coronary atherosclerosis in lupus patients.
Cellular infiltration analysis with digital cytometry
| Immune Cell Type | SLEAt (n = 38) | HC (n = 42) | SLE (n = 63) |
|---|---|---|---|
| CD8+ T Cells | 0.016 ± 0.001 | 0.032 ± 0.005 | 0.042 ± 0.004 |
| CD4+ Naïve T Cells | 0.075 ± 0.004 | 0.081 ± 0.008 | 0.135 ± 0.008 |
| CD4+ Resting Memory T Cells | 0.045 ± 0.007 | 0.105 ± 0.010 | 0.001 ± 0.000 |
| CD4+ Activated Memory T Cells | 0.036 ± 0.002 | 0.036 ± 0.005 | 0.063 ± 0.002 |
| Regulatory T Cells | 0.000 ± 0.000 | 0.000 ± 0.000 | 0.001 ± 0.000 |
| Resting NK Cells | 0.019 ± 0.002 | 0.055 ± 0.010 | 0.121 ± 0.005 |
| Activated NK Cells | 0.001 ± 0.000 | 0.004 ± 0.001 | 0.000 ± 0.000 |
| Monocytes | 0.292 ± 0.133 | 0.236 ± 0.011 | 0.160 ± 0.006 |
| Neutrophils | 0.413 ± 0.015 | 0.348 ± 0.010 | 0.394 ± 0.015 |
SLEAt: Lupus patients with atherosclerosis, HC: Healthy controls, SLE: lupus patients without atherosclerosis.
Conclusion: In this study, 10 hub genes for coronary atherosclerosis in lupus patients were found. Moreover, Digital cytometry and post hoc test identified different patterns immune cells in peripheral blood depending on the phenotype of the patient. These findings elucidate some of the molecular mechanisms involved in coronary atherosclerosis in a cohort of lupus patients. Further investigation is necessary to widen the knowledge on the molecular mechanisms underlying accelerated coronary atherosclerosis.
REFERENCES: [1] Reiss, Allison B et al. “Understanding Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Toward Better Treatment and Prevention.” Inflammation vol. 44,5 (2021): 1663-1682. doi:10.1007/s10753-021-01455-6.
[2] Jha, Surajkumar B et al. “Systemic Lupus Erythematosus and Cardiovascular Disease.” Cureus vol. 14,2 e22027. 8 Feb. 2022, doi:10.7759/cureus.22027.
Acknowledgements: NIL.
Disclosure of Interests: None declared.