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. 2021 Oct:187:106390.
doi: 10.1016/j.rmed.2021.106390. Epub 2021 Apr 5.

Genomic biomarkers in chronic beryllium disease and sarcoidosis

Nancy W Lin  1 , Lisa A Maier  2 , Margaret M Mroz  3 , Sean Jacobson  4 , Kristyn MacPhail  5 , Sucai Liu  6 , Zhe Lei  7 , Briana Q Barkes  8 , Tasha E Fingerlin  9 , Nabeel Hamzeh  10 , Annyce S Mayer  11 , Clara I Restrepo  12 , Divya Chhabra  13 , Ivana V Yang  14 , Li Li  15
Affiliations

Genomic biomarkers in chronic beryllium disease and sarcoidosis

Nancy W Lin et al. Respir Med. 2021 Oct.

Abstract

Background Previous gene expression studies have identified genes IFNγ, TNFα, RNase 3, CXCL9, and CD55 as potential biomarkers for sarcoidosis and/or chronic beryllium disease (CBD). We hypothesized that differential expression of these genes could function as diagnostic biomarkers for sarcoidosis and CBD, and prognostic biomarkers for sarcoidosis. Study Design/Methods We performed RT-qPCR on whole blood samples from CBD (n = 132), beryllium sensitized (BeS) (n = 109), and sarcoidosis (n = 99) cases and non-diseased controls (n = 97) to determine differential expression of target genes. We then performed logistic regression modeling and generated ROC curves to determine which genes could most accurately differentiate: 1) CBD versus sarcoidosis 2) CBD versus BeS 3) sarcoidosis versus controls 4) non-progressive versus progressive sarcoidosis. Results CD55 and TNFα were significantly upregulated, while CXCL9 was significantly downregulated in CBD compared to sarcoidosis (p < 0.05). The ROC curve from the logistic regression model demonstrated high discriminatory ability of the combination of CD55, TNFα, and CXCL9 to distinguish between CBD and sarcoidosis with an AUC of 0.98. CD55 and TNFα were significantly downregulated in sarcoidosis compared to controls (p < 0.05). The ROC curve from the model showed a reasonable discriminatory ability of CD55 and TNFα to distinguish between sarcoidosis and controls with an AUC of 0.86. There was no combination of genes that could accurately differentiate between CBD and BeS or sarcoidosis phenotypes. Interpretation CD55, TNFα and CXCL9 expression levels can accurately differentiate between CBD and sarcoidosis, while CD55 and TNFα expression levels can accurately differentiate sarcoidosis and controls.

Keywords: Chronic beryllium disease; Gene expression; Genomic biomarkers; Granulomatous lung disease; Sarcoidosis.

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Conflict of interest statement

Summary Declaration of Interest Statements

Dr. Yang reports consultant fees from Eleven P15, outside the submitted work.

Financial/nonfinancial disclosures:

Dr. Ivana V. Yang reports consultant fees from Eleven P15, outside the submitted work.

Figures

Figure 1:
Figure 1:
Differential Gene Expression Among Cases and Controls: Controls (Con), Chronic Beryllium Disease (CBD), Beryllium Sensitization (BeS), Sarcoidosis (Sarc). Boxplots show median, 25th and 75th percentile, and minimum and maximum gene expression levels for A) CD55 B) CXCL9 C) IFNγ D) RNase 3 E)TNFα. *p<0.05, **p<0.01, ***p<0.001
Figure 2:
Figure 2:
A) Logistic regression model including genes with significant differential expression and B) ROC curve demonstrating ability of CD55, TNFα, and CXCL9 to predict CBD versus sarcoidosis diagnosis w/ AUC of 0.98. TPR = true positive rate. FPR = false positive rate.
Figure 3:
Figure 3:
A) Logistic regression model including genes with significant differential expression and B) ROC curve demonstrating ability of CD55 and TNFα to predict sarcoidosis versus control diagnosis w/ AUC 0.86. TPR = true positive rate. FPR = false positive rate.
See this image and copyright information in PMC

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