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. 2022 Feb;77(2):186-190.
doi: 10.1136/thoraxjnl-2021-217315. Epub 2021 Sep 14.

Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis

William Whalen  1 , Mustafa Buyukozkan  2 , Bethany Moore  3 , Jong-Seok Moon  4 , Charles S Dela Cruz  5   6 , Fernando J Martinez  1 , Augustine M K Choi  1 , Jan Krumsiek  2 , Heather Stout-Delgado  1 , Soo Jung Cho  7
Affiliations

Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis

William Whalen et al. Thorax. 2022 Feb.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear aetiology and poorly understood pathophysiology. Although plasma levels of circulating cell-free DNA (ccf-DNA) and metabolomic changes have been reported in IPF, the associations between ccf-DNA levels and metabolic derangements in lung fibrosis are unclear. Here, we demonstrate that ccf-double-stranded DNA (dsDNA) is increased in patients with IPF with rapid progression of disease compared with slow progressors and healthy controls and that ccf-dsDNA associates with amino acid metabolism, energy metabolism and lipid metabolism pathways in patients with IPF.

Trial registration: ClinicalTrials.gov NCT01071707.

Keywords: idiopathic pulmonary fibrosis.

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Conflict of interest statement

Competing interests: FJM reports personal fees for advisory board work, non-financial support for travel and other from AstraZeneca, other (steering committee work and publication) from Abvie, Boehringer Ingelheim, BristolMyersSquibb, Bridge Biotherapeutics, CsL Behring, DevPro, Genentech, IQVIA, Sanofi, Shionogi, twoXAR, and Veracyte. FJM has served on Steering Committees for ILD studies supported by Afferent/Merck, Bayer, Biogen, NHLBI, Nitto, Novartis, Patara/Respivant, ProMedior/Roche, and Veracyte. FJM has participated in DSMB for studies supported by Biogen and Boehringer Ingelheim. FJM has been supported for study related travel by Boehringer Ingelheim, CsL Behring and Patara/Respivant. FJM has presented nonpromotional presentations for the Academy for Continuing Healthcare Learning, the American College of Chest Physicians, Boehringer Ingelheim, Brooklyn Methodist Hospital, National Association of Managed Care Physicians, Paradigm Communications, PeerView, United Therapeutics, and Vindico. AMKC is a cofounder and equity stockholder for Proterris, which develops therapeutic uses for carbon monoxide. AMKC has a use patent on CO and in COPD. All other authors have no conflicts of interest.

Figures

Figure 1
Figure 1
Study design and the circulating cell-free double-stranded DNA (ccf-­dsDNA) levels in plasma from patients with IPF. (A) Schematic diagram representing overall study design. (B) Demographics and baseline characteristics of patients with IPF and controls. (C) Quantification of ccf­-dsDNA concentration of plasma from patients with IPF and controls. Data are mean±SEM. *p< 0.05 using analysis of variance (ANOVA). IPF, idiopathic pulmonary fibrosis.
Figure 2
Figure 2
(A) Hierarchical clustering of Kendall’s Tau coefficients calculated for correlations between abundances of dsDNA concentration (rows) and metabolites (columns) in the pairwise fashion, using data from n=98 IPF plasma samples. (B) ccf-­dsDNA concentration in group 1 and group 2 defined by the hierarchical clustering. *p<0.05 by Student’s t-test. (C) Metabolome KEGG enrichment analysis of plasma from patients with IPF. Count=number of hits per pathway, p value<0.05. ccf-dsDNA, cell-free double-stranded DNA; IPF, idiopathic pulmonary fibrosis; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 3
Figure 3
The linear regression graph showing significant metabolites in selected pathways using univariate linear regression. Amino acid metabolism pathways (A), energy metabolism pathways (B) and sphingolipid metabolism pathway (C) are associated with ccf-­dsDNA levels. ccf-dsDNA, cell-free double-stranded DNA.
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References

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