Identification of diagnostic biomarkers and therapeutic targets in peripheral immune landscape from coronary artery disease

Xiaoteng Feng; Yifan Zhang; Min Du; Sijin Li; Jie Ding; Jiarou Wang; Yiru Wang; Ping Liu

doi:10.1186/s12967-022-03614-1

Identification of diagnostic biomarkers and therapeutic targets in peripheral immune landscape from coronary artery disease

J Transl Med. 2022 Sep 5;20(1):399. doi: 10.1186/s12967-022-03614-1.

Authors

Xiaoteng Feng¹, Yifan Zhang¹, Min Du¹, Sijin Li¹, Jie Ding¹, Jiarou Wang¹, Yiru Wang¹, Ping Liu²

Affiliations

¹ Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. liuping0207@yeah.net.

Abstract

Background: Peripheral biomarkers are increasingly vital non-invasive methods for monitoring coronary artery disease (CAD) progression. Their superiority in early detection, prognosis evaluation and classified diagnosis is becoming irreplaceable. Nevertheless, they are still less explored. This study aimed to determine and validate the diagnostic and therapeutic values of differentially expressed immune-related genes (DE-IRGs) in CAD.

Methods: We downloaded clinical information and RNA sequence data from the GEO database. We used R software, GO, KEGG and Cytoscape to analyze and visualize the data. A LASSO method was conducted to identify key genes for diagnostic model construction. The ssGSEA analysis was used to investigate the differential immune cell infiltration. Besides, we constructed CAD mouse model (low-density lipoprotein receptor deficient mice with high fat diet) to discover the correlation between the screened genes and severe CAD progress. We further uncovered the role of IL13RA1 might play in atherosclerosis.

Results: A total of 762 differential genes were identified between the peripheral blood of 218 controls and 199 CAD patients, which were significantly associated with infection, immune response and neural activity. 58 DE-IRGs were obtained by overlapping the differentially expressed genes(DEGs) and immune-related genes downloaded from ImmpDb database. Through LASSO regression, CCR9, CER1, CSF2, IL13RA1, INSL5, MBL2, MMP9, MSR1, NTS, TNFRSF19, CXCL2, HTR3C, IL1A, and NR4A2 were distinguished as peripheral biomarkers of CAD with eligible diagnostic capabilities in the training set (AUC = 0.968) and test set (AUC = 0.859). The ssGSEA analysis showed that the peripheral immune cells had characteristic distribution in CAD and also close relationship with specific DE-IRGs. RT-qPCR test showed that CCR9, CSF2, IL13RA1, and NTS had a significant correlation with LDLR^-/- mice. IL13RA1 knocked down in RAW264.7 cell lines decreased SCARB1 and ox-LDL-stimulated CD36 mRNA expression, TGF-β, VEGF-C and α-SMA protein levels and increased the production of IL-6, with downregulation of JAK1/STAT3 signal pathway.

Conclusions: We constructed a diagnostic model of advanced-stage CAD based on the screened 14 DE-IRGs. We verified 4 genes of them to have a strong correlation with CAD, and IL13RA1 might participate in the inflammation, fibrosis, and cholesterol efflux process of atherosclerosis by regulating JAK1/STAT3 pathway.

Keywords: Coronary atherosclerotic disease; Immune cells; Immune-related genes; Inflammation; Peripheral blood.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis* / genetics
Biomarkers / metabolism
Coronary Artery Disease* / genetics
Gene Expression Profiling
Mice
Signal Transduction / genetics

Substances

Biomarkers