BATF2 and PDK4 as diagnostic molecular markers of sarcoidosis and their relationship with immune infiltration

Sarcoidosis (SA) is an immune disorder disease featuring granulomas formation with a controversial etiopathogenesis. We aimed to uncover potential markers for SA diagnosis and explore how immune cell infiltration contributes to the pathogenesis of SA.

Sarcoidosis GSE83456 samples and GSE42834 from Gene Expression Omnibus (GEO) were analyzed as the training and external validation sets, respectively. Firstly, R statistical software was employed to uncover the differentially expressed genes (DEGs) of GSE83456. Weighted gene co-expression network analysis (WGCNA) was used to reveal the key module of DEGs. Secondly, the genes of the key module were used to analyze functional correlations. Thirdly, support vector machine (SVM) algorithms and least absolute shrinkage and selection operator (LASSO) logistic regression were applied for screening and verification of the diagnostic markers for key module genes. Finally, the infiltration of immune cells in SA patients' blood samples was assessed by Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), after which correlations of diagnostic markers immune cell and infiltration were explored. Serum samples collected from human research participants were used for confirmatory analysis of bioinformatics. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of BATF2 and PDK4.

In total, 580 DEGs were identified from the key module. The genes PDK4 [area under the curve (AUC) =0.942] and BATF4 (AUC =0.980) were revealed as diagnostic markers of SAs. The diagnostic power of the 2 genes was verified in GSE42834. We found that monocytes, T cells regulatory (Tregs), mast cells, macrophages, natural killer (NK) cells, and dendritic cells (DC) may contribute to SA development through immune cell infiltration study. In addition, PDK4 and BATF4 were closely associated with these immune cells. Both BATF2 and PDK4 were highly expressed in active pulmonary SA. Using non-SA patients as controls, the AUC of serum PDK4, BATF2, and their combination for the diagnosis of active pulmonary SA was 0.798 (95% CI: 0.701 to 0.876), 0.895 (95% CI: 0.813 to 0.950), and 0.910 (95% CI: 0.831 to 0.960), respectively.

The genes PDK4 and BATF4 could be used as diagnostic markers of active pulmonary SA. Immune cell infiltration severs an important role in SA.