Serum amino acid concentrations and clinical outcomes in smokers: SPIROMICS metabolomics study

Abstract

Metabolomics is an emerging science that can inform pathogenic mechanisms behind clinical phenotypes in COPD. We aimed to understand disturbances in the serum metabolome associated with respiratory outcomes in ever-smokers from the SPIROMICS cohort. We measured 27 serum metabolites, mostly amino acids, by 1H-nuclear magnetic resonance spectroscopy in 157 white ever-smokers with and without COPD. We tested the association between log-transformed metabolite concentrations and one-year incidence of respiratory exacerbations after adjusting for age, sex, current smoking, body mass index, diabetes, inhaled or oral corticosteroid use, study site and clinical predictors of exacerbations, including FEV1% predicted and history of exacerbations. The mean age of participants was 53.7 years and 58% had COPD. Lower concentrations of serum amino acids were independently associated with 1-year incidence of respiratory exacerbations, including tryptophan (β = -4.1, 95% CI [-7.0; -1.1], p = 0.007) and the branched-chain amino acids (leucine: β = -6.0, 95% CI [-9.5; -2.4], p = 0.001; isoleucine: β = -5.2, 95% CI [-8.6; -1.8], p = 0.003; valine: β = -4.1, 95% CI [-6.9; -1.4], p = 0.003). Tryptophan concentration was inversely associated with the blood neutrophil-to-lymphocyte ratio (p = 0.03) and the BODE index (p = 0.03). Reduced serum amino acid concentrations in ever-smokers with and without COPD are associated with an increased incidence of respiratory exacerbations.

Conflict of interest statement

WWL, TG, SM, JLC, APC, LY, REK, RP, MLNM, SPP, WKO, WD, BH, TJS and KAS declare no competing interests. RPB serves on the advisory boards of GSK, BI and Mylan, and received research grants from GSK and BI. RGB reports grants from NIH during the conduct of the study; grants from Alpha1 Foundation, Foundation for the NIH, and COPD Foundation and personal fees from UpToDate outside the submitted work. N. N. H. serves on the advisory board of AstraZeneca, GlaxoSmithKline, and Mylan, and has received research grants fromAstraZeneca, Boehringer-Ingelheim Pharmaceuticals, Inc, Forest Research Institute, Inc, and GlaxoSmithKline. CBC reports grants from Equinox Health Clubs, personal fees from Equinox Health Clubs, grants from Amgen, personal fees from PulmonX, other from GlaxoSmithKline and part-time employment in scientific engagement for the GlaxoSmithKline Global Respiratory Franchise. IB reports personal fees from Astra Zeneca, grants from GE Healthcare, personal fees from Grifols, personal fees from CSL Behring, grants from Amgen, grants from PCORI. JAK reported serving on a data monitoring committee for Sanofi and receiving grants from the National Institutes of Health and the Patient-Centered Outcomes Research Institute. PGW reports personal fees from AstraZeneca, Theravance, Regeneron, Sanofi, Genentech, and Novartis. FJM reports personal fees and non-financial support from American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, Continuing Education, ConCert, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, National Association for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Chiesi, Roche, Sunovion, and Theravance; non-financial support from ProterrixBio; personal fees from Columbia University, Haymarket Communications, Integritas, Inthought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/MedScape, Western Connecticut Health Network, and American Thoracic Society. MKH reports personal fees from GSK, personal fees from BI, personal fees from AZ, other from Novartis, other from Sunovion.

Figures

Figure 1

Radar plot showing mean-centered and range-scaled log-transformed metabolite concentrations by exacerbation group. Asterisks (*) denote statistical significance at the 10% false discovery rate.

Figure 2

Volcano plot showing the adjusted association between log-transformed metabolite concentrations and incident respiratory exacerbations. Red dots represent metabolites that are statistically significant at the 10% false discovery rate. Black dots represent metabolites that are not statistically significant.

Figure 3

Volcano plots showing the association between log-transformed metabolite concentrations and FEV1% predicted (A), % low attenuation area (LAA) <−950 Hounsfield Units (HU) on chest computed tomography (CT) (B), and 6-minute walking distance (C). Black dots represent individual metabolites.