Causal genes identification of giant cell arteritis in CD4+ Memory t cells: an integration of multi-omics and
Insights
Giant cell arteritis (GCA) risk is linked to CD4+ Memory T cells. DDIT4 gene promotes GCA by causing chronic inflammation in these cells, highlighting its role in disease development.
Area of Science:
- Immunology
- Genetics
- Vascular Biology
Background:
- Giant cell arteritis (GCA) is a common age-related vasculopathy.
- The specific role of CD4+ Memory T cells in GCA pathogenesis remains unclear.
Purpose of the Study:
- To elucidate the role of CD4+ Memory T cells in GCA.
- To identify genes causally associated with GCA risk within CD4+ Memory T cells.
Main Methods:
- Single-cell analysis of CD4+ Memory T cells from GCA patients.
- Mendelian randomization and eQTL analysis to identify causal genes.
- In vitro experiments using Jurkat cell lines to validate gene function.
Main Results:
- DDIT4 and ARHGAP15 identified as significant risk genes for GCA.
- Single-cell analysis revealed differences in intercellular communication, metabolism, and drug sensitivity based on DDIT4/ARHGAP15 expression.
- In vitro studies showed DDIT4 induces a chronic, low-intensity inflammatory state in CD4+ Memory T cells, promoting GCA.
Conclusions:
- DDIT4 and ARHGAP15 are causally linked to GCA risk.
- DDIT4 promotes GCA by inducing chronic inflammation in CD4+ Memory T cells.
Background:
Giant cell arteritis (GCA) is a prevalent artery and is strongly correlated with age. The role of CD4+ Memory T cells in giant cell arteritis has not been elucidated.
Method:
Through single-cell analysis, we focused on the CD4+ Memory T cells in giant cell arteritis. eQTL analysis and mendelian randomization analysis identified the significant genes which have a causal effect on giant cell arteritis risk. CD4+ Memory T cells were subsequently divided into gene-positive and gene-negative groups, then further single-cell analysis was conducted. Mendelian randomization of plasma proteins, blood-urine biomarkers and metabolites were also performed. Eventually, the PMA induced Jurkat cell lines were used for biological experiments to explore the specific functions of significant causal genes in CD4+ Memory T cells.
Results:
Similarity of CD4+ Memory T cells in GCA and old samples were explored. DDIT4 and ARHGAP15 were identified as significant risk genes via mendelian randomization. The CD4+ Memory T cells were then divided into DDIT4 ± or ARHGAP15 ± groups, and further single-cell analysis indicated the differences in aspects involving intercellular communication, functional pathways, protein activity, metabolism and drug sensitivity between positive and negative groups. In vitro experiments, including overexpression and knockdown, demonstrated that DDIT4 leading to a chronic, low-intensity inflammatory state in CD4+ Memory T cells, eventually promoting the development of GCA.
Conclusion:
DDIT4 and ARHGAP15 have significant causal effects on giant cell arteritis risk. Specifically, DDIT4 exhibit pro-inflammatory effects on GCA via promotes chronic, low-intensity inflammatory in CD4+ Memory T cell.
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