Prioritizing Therapeutic Targets for Interstitial Lung Disease: A Causal Mediation Analysis.

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.