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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.