Plasma Mitochondrial DNA is Associated with Extrapulmonary Sarcoidosis

Sarcoidosis is an unpredictable granulomatous disease in which African-Americans (AAs) disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis. Extracellular mtDNA concentrations were measured using qPCR for the human MT-ATP6 gene on bronchoalveolar (BAL) and plasma samples from healthy control and sarcoidosis subjects from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding Stage, extrapulmonary disease, and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort. Relative to Controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL and plasma, particularly in the plasma of subjects with extrapulmonary disease. Relative to Caucasians, AAs displayed excessive MT-ATP6 concentrations in the BAL and plasma, where the latter compartment correlated with significantly high odds of extrapulmonary disease. Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and AA descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.