Abstract Rationale Higher ratios of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) have been associated with inflammation and lower lung function, yet specific molecular mechanisms are unknown. Elucidating PUFA interactions with protein biomarkers in relation to lung function may provide mechanistic insights on the inflammatory effects of PUFAs. Methods We evaluated spirometric, proteomic and PUFA biomarker data from 3727 participants from the 5-year follow-up visit of the Genetic Epidemiology of COPD (COPDGene) Study. Proteomic data were measured in plasma using the SomaScan 5K aptamer-based assay for 4979 SOMAmers representing 4860 unique proteins. Plasma PUFAs were quantified by gas chromatography-mass spectrometry. Proteomic interactions with total omega-6, total omega-3 and the ratio of omega 6:3 PUFAs were estimated for FEV1 cross-sectionally using robust linear regression. Causal mediation of PUFA effects through protein levels were evaluated for significant (FDR 0.1) PUFA-protein interactions. All models adjusted for age, sex, height, ancestry PCs, smoking variables, WBCs, platelets and study center. Results We identified nine significant PUFA-protein interactions for FEV1, all with the omega 6:3 ratio. For seven proteins (PAPP-A, RSPO1, CRDL1, COAA1, DRGX, PTN, ILT-2), we observed negative interaction effects, whereby higher levels of the proteins were associated with greater adverse effects of omega 6:3 on FEV1; for two proteins (CAD17, AGR3), we observed positive interaction effects. In prospective analysis of FEV1 at the 10-year follow-up visit, the interaction effects were robust for PAPP-A and were nominally significant (p 0.05) for RSPO1, CRDL1, DRGX, ILT-2, CAD17 and AGR3. Mediation analysis revealed significant causal mediated effects through PAPP-A, RSPO1, CRDL1 and CAD17. For PAPP-A or pregnancy-associated plasma protein-A, a known inflammatory protein with a role in insulin growth factor and nuclear factor-kappa B pathway activation, higher omega 6:3 ratios were associated with higher PAPP-A (p = 1.21e-11), which mediated 10% (p = 0.002) of the adverse effect of the omega 6:3 ratio on FEV1. Further evaluation of PAPP-A showed significantly higher levels in participants with COPD versus controls (9.38 vs 9.24 relative fluorescence units, p 2e-16), with increasing levels associated with more severe disease (p-trend across GOLD stages=0.009). Conclusion Inflammatory proteins such as PAPP-A may mediate associations of the omega 6:3 ratio with FEV1 and contribute to chronic lung disease. These findings shed light on molecular mechanisms underlying PUFA nutritional status and lung function, and have implications for precision dietary strategies to promote lung health. This abstract is funded by: NIH
Patchen et al. (Fri,) studied this question.