Understanding Sarcoidosis Susceptibility and Disease Burden Through Multi Omics - ABSTRACT Sarcoidosis is a systemic granulomatous disease with striking heterogeneity of clinical course and increasing mortality and morbidity rates. Diagnosis is difficult and predicting disease outcomes is virtually impossible. While it is known that sarcoidosis likely involves host genetic susceptibility and a dysregulated immune response to any number of environmental factors, the mechanisms by which granulomas form and the determinants of severity and disease manifestations remain elusive. Our team has been at the forefront of genetics and transcriptomics in sarcoidosis, including the identification of genes for susceptibility, severity, ancestry- and organ-specific effects, the first and only single-cell RNA sequencing study of sarcoidosis and the first GWAS of pulmonary fibrosis in patients of African ancestry (AA). These findings provide the foundation for further dissection of cellular mechanisms that lead to systemic immune dysregulation and tissue-specific inflammatory response. Our current proposal will advance the field by filling critical gaps in sarcoidosis research, including the lack of mechanism and biomarkers for sarcoidosis and its patient-specific disease burden, poor consensus of existing genetic and genomic studies, and the absence of mechanistic connections between immune profiles in the periphery and affected organs. We will exploit the clinical, immunological, genomic, and bioinformatic expertise of our team to apply an innovative, and integrative multi-omic approach to fil these gaps. Specifically, in Aim 1, we will use high-througput plasma proteomics from over 1000 sarcoidosis patients of AA and European ancestry (EA), 800 healthy and 275 diseased controls to a) distinguish sarcoidosis patients from healthy and other immune-mediated disease controls, b) to distinguish patients with high disease burden from those with low disease burden, and c) elucidate ancestry and disease course specific mechanisms and biomarkers. In Aim 2, we will identify candidate genes for susceptibility to and disease burden of sarcoidosis by a) Conducting a large TWAS of over 2,000 EA and AA patients compared to 3900 healthy controls, and b) replication and characterization of these effects via scRNAseq of an independent cohort, and c) prioritize transcriptomic effects via colocalization of genetic and QTL effects. Finally, in Aim 3, we will a) identify candidate genes that are differentially expressed in granulomas via spatial transcriptomics and whose protein products are dysregulated in bronchoalveolar lavage (BAL) and b) identify genes best suited for functional and drug target studies based on integrating the data collected across multiple biological systems and data types. The success of our work will be facilitated by the extensive genetic, genomic, and clinical data available to us from our own cohorts and the TOPMed Consortium (of which we are members) and its rigor supported by strong preliminary data indicative of novel therapies for AA and high disease burden patients.
