Lung proteome and metabolome endotype in HIV-associated obstructive lung disease

Methods

Bronchoalveolar lavage fluid (BALF) samples from 26 persons living with HIV with obstructive lung disease were matched to persons living with HIV without obstructive lung disease based on age, smoking status, and antiretroviral treatment. 6,414 proteins were measured using SomaScan aptamer-based assay. We used sparse distance-weighted discrimination (sDWD) to test for a difference in protein expression and permutation tests to identify univariate associations between proteins and forced expiratory volume in 1s precent predicted (FEV1pp).

Significant proteins were entered into a pathway overrepresentation analysis (ORA). We also constructed protein-driven endotypes using K-means clustering and performed ORA on the proteins that were significantly different between clusters. We compared protein-associated clusters to those obtained from BALF and plasma metabolomics data on the same patient cohort.

Results: After filtering, we retained 3872 proteins for further analysis. Based on sDWD, protein expression was able to separate cases and controls. We found 575 proteins that were significantly correlated with FEV1pp after multiple comparisons adjustment.

We identified two protein-driven endotypes, one of which was associated with poor lung function, and found that insulin and apoptosis pathways were differentially represented. We found similar clusters driven by metabolomics in BALF but not plasma. Conclusion: Protein expression differs in persons living with HIV with and without obstructive lung disease.

We were not able to identify specific pathways differentially expressed among patients based on FEV1pp; however, we identified a unique protein endotype associated with insulin and apoptotic pathways.