Functional link between sarcoidosis-associated gene variants and quantitative levels of bronchoalveolar lavage fluid cell types.

Background: Sarcoidosis is an inflammatory disease that affects multiple organs. Cell analysis from bronchoalveolar lavage fluid (BALF) is a valuable tool in the diagnostic workup and differential diagnosis of sarcoidosis. Besides the expansion of lymphocyte expression-specific receptor segments (Vα2.3 and Vβ22) in some patients with certain HLA types, the relation between sarcoidosis susceptibility and BAL cell populations' quantitative levels is not well-understood.

Methods: Quantitative levels defined by cell concentrations of BAL cells and CD4/CD8 ratio were evaluated together with genetic variants associated with sarcoidosis in 692 patients with extensive clinical data. Genetic variants associated with clinical phenotypes, Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS), were examined separately. An association test linear regression using an additive model adjusted for sex, age, and correlated cell type was applied. To infer the biological function of genetic associations, enrichment analysis of expression quantitative trait (eQTLs) across publicly available eQTL databases was conducted.

Results: Multiple genetic variants associated with sarcoidosis were significantly associated with quantitative levels of BAL cells. Specifically, LS genetic variants, mainly from the HLA locus, were associated with quantitative levels of BAL macrophages, lymphocytes, CD3 cells, CD4 cells, CD8 cells, CD4/CD8 ratio, neutrophils, basophils, and eosinophils. Non-LS genetic variants were associated with quantitative levels of BAL macrophages, CD8 cells, basophils, and eosinophils. eQTL enrichment revealed an influence of sarcoidosis-associated SNPs and regulation of gene expression in the lung, blood, and immune cells.

Conclusion: Genetic variants associated with sarcoidosis are likely to modulate quantitative levels of BAL cell types and may regulate gene expression in immune cell populations. Thus, the role of sarcoidosis-associated gene-variants may be to influence cellular phenotypes underlying the disease immunopathology.