Multi-Omic Signatures of Sarcoidosis and Progression in Bronchoalveolar Lavage Cells

Abstract

Introduction: Sarcoidosis is a heterogeneous, granulomatous disease that can prove difficult to diagnose, with no accurate biomarkers of disease progression. Therefore, we profiled and integrated the DNA methylome, mRNAs, and microRNAs to identify molecular changes associated with sarcoidosis and disease progression that might illuminate underlying mechanisms of disease and potential genomic biomarkers. Methods: Bronchoalveolar lavage cells from 64 sarcoidosis subjects and 16 healthy controls were used. DNA methylation was profiled on Illumina HumanMethylationEPIC arrays, mRNA by RNA-sequencing, and miRNAs by small RNA-sequencing. Linear models were fit to test for effect of diagnosis and phenotype, adjusting for age, sex, and smoking. We built a supervised multi-omics model using a subset of features from each dataset. Results: We identified 46,812 CpGs, 1,842 mRNAs, and 5 miRNAs associated with sarcoidosis versus controls and 1 mRNA, SEPP1 - a protein that supplies selenium to cells, associated with disease progression. Our integrated model emphasized the prominence of the PI3K/AKT1 pathway in sarcoidosis, which is important in T cell and mTOR function. Novel immune related genes and miRNAs including LYST, RGS14, SLFN12L, and hsa-miR-199b-5p, distinguished sarcoidosis from controls. Our integrated model also demonstrated differential expression/methylation of IL20RB, ABCC11, SFSWAP, AGBL4, miR-146a-3p, and miR-378b between non-progressive and progressive sarcoidosis. Conclusions: Leveraging the DNA methylome, transcriptome, and miRNA-sequencing in sarcoidosis BAL cells, we detected widespread molecular changes associated with disease, many which are involved in immune response. These molecules may serve as diagnostic/prognostic biomarkers and/or drug targets, although future testing will be required for confirmation.

From Karl Wurm and Guy Scadding's staging to 18F-FDG PET/CT scan phenotyping and far beyond: perspective in the evading history of phenotyping in sarcoidosis

“…Given that sarcoidosis is a complex, polygenic disease of unknown cause with diverse clinical phenotypes, the “omics” approach adds another layer of information by delving into the molecular signatures that could provide important insights on the pathogenesis of this disease ( 4 , 5 , 41 , 82 – 88 ). Genetic predisposition and immune dysregulation, inherent to sarcoidosis, are investigated by characterizing both previously known and newly discovered immune-cell-specific pathways, gene expression, and epigenetic modifications that may differ between specific tissues and compartments as well as between progressive and non-progressive disease manifestations ( 41 , 89 – 94 ). Through “omics,” we have currently gained access to a very advanced group of techniques that can provide conceptual, mechanistic, and molecular interpretations of phenotypes irrespective of treatment.…”