Derivation of a peripheral blood-based transcriptomic risk score for extrapulmonary sarcoidosis

Extrapulmonary sarcoidosis can be identified in many tissues but as an unpredictable display in an already rare disease, has not been methodically examined. We sought to identify gene-expression differences in blood and derive a transcriptomic risk score (TRS) to predict extrapulmonary manifestations of sarcoidosis.

We used RNA sequencing data from the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study and a cohort from our institution. We performed differential expression mega-analysis as well as pathway enrichment and cell-type deconvolution comparing individuals with pulmonary-only sarcoidosis to those with extrapulmonary sarcoidosis. In addition, we deployed supervised learning models to develop the TRS to distinguish extrapulmonary sarcoidosis from pulmonary-only disease.

We identified 594 genes that met the nominal significance threshold for differential expression. In the local cohort, we found that individuals with extrapulmonary sarcoidosis had a significantly lower proportion of estimated naïve and memory B cells. The TRS had moderate predictive ability for extrapulmonary sarcoidosis in the held-out testing sample (AUC 0.72) but only modest predictive ability (AUC 0.58) in the independent dataset.

Our study demonstrates that a TRS derived from blood-based transcriptomics is able to distinguish between individuals with pulmonary-only and extrapulmonary sarcoidosis. The TRS is also comprised of biologically relevant genes, including several T cell receptor alpha subunit genes. Future studies are needed to prospectively validate our findings and potentially expand their use to identify precision treatments for individuals with extrapulmonary sarcoidosis.