Rationale The biochemical mechanisms underlying lung function are incompletely understood.
Objectives To identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery—the European Prospective Investigation into Cancer–Norfolk (EPIC-Norfolk, n=10 460) and validation—the VA Normative Aging Study (NAS) metabolomic cohort (n=437).
Methods We ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and p<0.05.
Measurements and main results Of 156 metabolites that associated with FEV1 in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV1/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV1 and FEV1/FVC.
Conclusions The validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.
- clinical epidemiology
- oxidative stress
- respiratory measurement
- systemic disease and lungs
Data availability statement
Data are available upon reasonable request. Data are available on request with agreement from all coauthors and funding bodies.
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RSK and IDS are joint first authors.
Contributors Conceptualisation: RSK, JL-S, IS and CL; methodology: RSK, JL-S, PV, NW and CL; validation: PK and HMK; formal analysis: RSK, HB and IS; investigation and resources: AS, PV, DS, SW, AL, NW, CL and JL-S; data curation: HB, AL and IS; writing—original draft preparation: RSK, HB, JL-S, IS and CL; writing—review and editing: PK, AS, PV, DS, SW, HMK, AL and NW; supervision: PV, SW, AL, NW, CL and JL-S; funding acquisition: RSK, JL-S, AS, PV, DS and CL.
Funding This study was supported by PR161204 W81XWH-17-1-0533 from the Congressionally Directed Medical Research Programmes, USAMRDC. The VA Normative Aging Study is a research component of the Massachusetts Veterans Epidemiology Research and Information Centre at VA Boston Healthcare System and is supported by the Cooperative Studies ProgramProgramme/Epidemiology Research and Information Centres, Office of Research and Development, US Department of Veterans Affairs (grant number not applicable). AS was supported by a Senior Research Career Scientist award from the Clinical Science Research and Development Service, Office of Research and Development, US Department of Veterans Affairs (grant number not applicable). RSK was supported by K01HL146980 from the National Heart, Lung, and Blood Institute (NHLBI). PK was supported by P01HL132825 from the National Institutes of Health/NHLBI. JL-S was supported by R01HL123915, R01HL141826 and P01HL132825. HMK was supported by the Jane and Aatos Erkko Foundation, the Paulo Foundation and the Paediatric Research Foundation (grant number not applicable). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement number 115 372.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.