Sarcoidosis Related Novel Candidate Genes Identified by Multi-Omics Integrative Analyses

Abstract

Sarcoidosis is a multifactorial systemic disease characterized by granulomatous inflammation and greatly impacting on global public health. The etiology and mechanisms of sarcoidosis are not fully understood. Recent high-throughput biological research has generated vast amounts of multi-omics big data on sarcoidosis, but their significance remains to be determined. We sought to identify novel candidate regions, and genes consistently altered in heterogeneous omics studies so as to reveal the underlying molecular mechanisms. We conducted a comprehensive integrative literature analysis on global data on sarcoidosis, including genomic, transcriptomic, proteomic, and phenomic studies. We performed positional integration analysis of 38 eligible datasets originating from 17 different biological layers. Using the integration interval length of 50 kb, we identified 54 regions reaching significance value p ≤ 0.0001 and 15 regions with significance value p ≤ 0.00001, when applying more stringent criteria. Secondary literature analysis of the top 20 regions, with the most significant accumulation of signals, revealed several novel candidate genes for which associations with sarcoidosis have not yet been established, but have considerable support for their involvement based on omic data. These new plausible candidate genes include NELFE, CFB, EGFL7, AGPAT2, FKBPL, NRC3, and NEU1. Furthermore, annotated data were prepared to enable custom visualization and browsing of these sarcoidosis related omics evidence in the University of California Santa Cruz (UCSC) Genome Browser. Further multi-omics approaches are called for sarcoidosis biomarkers and diagnostic and therapeutic innovation. Our approach for harnessing multi-omics data and the findings presented herein reflect important steps toward understanding the etiology and underlying pathological mechanisms of sarcoidosis.

Presence of Antibodies Binding to Negative Elongation Factor E in Sarcoidosis

“…Hočevar et al published recently a statistical analysis of genome-wide association study (GWAS). GWAS signals could be found increased in the region of NELF-E, SKIV2L, and STK19 genes [28]. In our study, we found only for NELF-E but not for SKIV2L or STK19 autoantibodies in sarcoid patients.…”

Sarcoidosis: Causes, Diagnosis, Clinical Features, and Treatments

“…Integration of different omics data presents comprehensive overviews of pathological molecular pathways that can be targeted for the development and application of precision medicine [200]. Multi-omics integrative analysis generates vast amounts of big data from sarcoidosis samples including genomic, transcriptomics, proteomic, and phenomic studies, all of which have been used to describe novel candidate regions and genes, altered in sarcoidosis [201]. These new data analysis methods are bridging the gap between conventional therapies and advanced care and are bound to open new therapeutic paradigms for this complex disease.…”

Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders

“…One of those is located in a TPR domain ( Andreoletti et al, 2017 ). Variation in the cochaperones encoded by PTGES3L and FKBPL has also been potentially linked to various inflammatory disease ( Hocevar et al, 2018 ; Bianchi et al, 2021 ), but more analysis is required. Single-nucleotide variants in the HSP90AB1 and HSP90B1 genes have been proposed to modulate chronic obstructive pulmonary disease ( Ambrocio-Ortiz et al, 2021 ), and Hsp90 is known to regulate inflammatory processes ( Nizami et al, 2021 ).…”