Blood Gene Expression Risk Profiles and Interstitial Lung Abnormalities: COPDGene and ECLIPSE cohort studies

Rationale Interstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Blood gene expression profiles can predict IPF mortality, but whether these same genes associate with ILA and ILA outcomes is unknown. Objectives To evaluate if a previously described blood gene expression profile associated with IPF mortality is associated with ILA and all-cause mortality. Methods In COPDGene and ECLIPSE study participants with visual scoring of ILA and gene expression data, we evaluated the association of a previously described IPF mortality score with ILA and mortality. We also trained a new ILA score, derived using genes from the IPF score, in a subset of COPDGene. We tested the association with ILA and mortality on the remainder of COPDGene and ECLIPSE. Measurements and Main Results In 1,469 COPDGene (training n=734; testing n=735) and 571 ECLIPSE participants, the IPF score was not associated with ILA or mortality. However, an ILA score derived from IPF score genes was associated with ILA (meta-analysis of test datasets OR 1.4 [95% CI: 1.2-1.6]) and mortality (HR 1.25 [95% CI: 1.12-1.41]). Six of the 11 genes in the ILA score had discordant directions of effects compared to the IPF score. The ILA score partially mediated the effects of age on mortality (11.8% proportion mediated). Conclusions An ILA gene expression score, derived from IPF mortality-associated genes, identified genes with concordant and discordant effects on IPF mortality and ILA. These results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death. Key messages What is the key question Interstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Do blood gene expression profiles that predict IPF mortality also associate with ILA? What is the bottom line An ILA gene expression score, derived from IPF mortality-associated genes, was associated with ILA and all-cause mortality. This score identified genes with concordant and discordant effects on IPF mortality and ILA. Our results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death. Why read on Our results lend insight into how gene expression profiles and biological pathways associated with IPF prognosis relate to ILA and all-cause mortality