Unique TGF-ß signaling pathway in African Americans with fibrotic sarcoidosis

Document Type

Conference Proceeding

Publication Date


Publication Title

Genetic Epidemiology


Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas in any number of organs, but with pulmonary manifestation in most patients. Progressive pulmonary disease (PPD), likely including pulmonary fibrosis (PF), leads to worse clinical outcomes and prognosis. Previous genome-wide association studies of PPD in sarcoidosis patients of European ancestry (EA) identified multiple associations with genes in the TGF-ß signaling pathway, specifically TGFß1, TGFß2, TGFß3, GREM1, and ANXA11. This is important as TGF-ß is widely accepted as a master regulator of fibrosis. The involvement of TGF-ß signaling has not previously been investigated in patients of African Ancestry (AA) nor has it been investigated beyond variant association. In this study we aimed to identify genetic and genomic factors influencing fibrotic disease in a cohort of AA patients with PF compared to non-fibrotic sarcoidosis patients using whole genome sequencing and cell-type specific expression data. We identified suggestive associations between variants in the region of TGFß3 as well as other TGF-ß pathway genes PARS2, LTBP1, PVT1, SLC29A3, OTX2-AS1/EXOC5, and SPOP; all of which are primarily involved in TGF-ß signaling and fibrosis or play a regulatory role. Single-cell RNA sequencing data were obtained and cell-type specific expression quantitative trait loci (eQTL) are being identified to better understand the role risk variants play in the mechanism of fibrotic development. Our findings support both the role of TGF-ß signaling in the development of PF as well as differences in the dysregulation of TGF-ß signaling by ancestry.





First Page