@article{Oldham:2026:rs.3.rs-8714555/v1,
author = {Oldham, J and Molyneaux, P and Maddali, M and Newton, C and Kim, J and Konkol, S and Pugashetti, J and Liu, G and Goobie, G and Adegunsoye, A and Ma, S-F and Bornstein, D and Murray, S and Wain, L and Saini, G and Stewart, I and Johnson, S and Jenkins, G and Strek, M and Linderholm, A and Chen, C-H and Fahy, W and Zemans, R and Moore, B and Khanna, D and Ryerson, C and Flaherty, K and Suresh, M and Hoffmann-Vold, A-M and Maher, T and Garcia, C and Wolters, P and Martinez, F and Noth, I and Smith, JA},
doi = {rs.3.rs-8714555/v1},
journal = {Res Sq},
title = {Prioritizing Therapeutic Targets for Interstitial Lung Disease: A Causal Mediation Analysis.},
url = {http://dx.doi.org/10.21203/rs.3.rs-8714555/v1},
year = {2026}
}

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TY  - JOUR
AB  - Progressive interstitial lung disease (ILD) leads to declining lung function and death. New therapies to treat ILD are urgently needed. Here we performed a secondary analysis of proteomic data from ten ILD cohorts across the United States, Canada, and United Kingdom. Causal mediation analysis was used to estimate the effect of plasma proteins previously linked to organ fibrosis in mechanistic studies (exposure) on survival (outcome) through lung function decline (mediator). Of 102 proteins tested in a discovery cohort (n = 1963), 47 were mediated by declining lung function. Of these 47 proteins, 7 showed sustained mediation in an independent validation cohort (n = 1172). Proteins with the strongest mediated effect were amphiregulin and integrin beta six. Sensitivity analysis showed that results were robust to unmeasured confounding. Here we provide epidemiological evidence implicating seven proteins as potentially causal of progressive ILD. These findings build upon mechanistic studies showing a causal link between these proteins and organ fibrosis, supporting their prioritization for therapeutic consideration.
AU  - Oldham,J
AU  - Molyneaux,P
AU  - Maddali,M
AU  - Newton,C
AU  - Kim,J
AU  - Konkol,S
AU  - Pugashetti,J
AU  - Liu,G
AU  - Goobie,G
AU  - Adegunsoye,A
AU  - Ma,S-F
AU  - Bornstein,D
AU  - Murray,S
AU  - Wain,L
AU  - Saini,G
AU  - Stewart,I
AU  - Johnson,S
AU  - Jenkins,G
AU  - Strek,M
AU  - Linderholm,A
AU  - Chen,C-H
AU  - Fahy,W
AU  - Zemans,R
AU  - Moore,B
AU  - Khanna,D
AU  - Ryerson,C
AU  - Flaherty,K
AU  - Suresh,M
AU  - Hoffmann-Vold,A-M
AU  - Maher,T
AU  - Garcia,C
AU  - Wolters,P
AU  - Martinez,F
AU  - Noth,I
AU  - Smith,JA
DO  - rs.3.rs-8714555/v1
PY  - 2026///
TI  - Prioritizing Therapeutic Targets for Interstitial Lung Disease: A Causal Mediation Analysis.
T2  - Res Sq
UR  - http://dx.doi.org/10.21203/rs.3.rs-8714555/v1
UR  - https://www.ncbi.nlm.nih.gov/pubmed/41674845
ER  - 

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