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Observational Study
. 2020 May 1;21(1):100.
doi: 10.1186/s12931-020-01336-w.

Heme metabolism genes Downregulated in COPD Cachexia

Ava C Wilson  1   2 , Preeti L Kumar  2 , Sool Lee  3 , Margaret M Parker  3 , Itika Arora  2 , Jarrett D Morrow  3 , Emiel F M Wouters  4 , Richard Casaburi  5 , Stephen I Rennard  6   7 , David A Lomas  8 , Alvar Agusti  9   10 , Ruth Tal-Singer  11 , Mark T Dransfield  2 , J Michael Wells  2 , Surya P Bhatt  2 , George Washko  12 , Victor J Thannickal  2 , Hemant K Tiwari  13 , Craig P Hersh  3   12 , Peter J Castaldi  3   12 , Edwin K Silverman  3   12 , Merry-Lynn N McDonald  14   15   16
Affiliations
Observational Study

Heme metabolism genes Downregulated in COPD Cachexia

Ava C Wilson et al. Respir Res. .

Abstract

Introduction: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

Methods: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m2) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m2 among women and < 17 kg/m2 among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.

Results: The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).

Discussion: Several replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage.

Keywords: Chronic obstructive pulmonary disease.

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Conflict of interest statement

ACW, PLK, SL, MMP, IA, HKT, VJT, GW, MW, AA, SR, and RC report no conflicts of interest. JM reports grants from NIH NHLBI, during the conduct of the study. EW reports board membership for Nycomed and Boehringer, grants from AstraZeneca and GlaxoSmithKline, and payment for lectures including service on speakers’ bureaus from GlaxoSmithKline, Novartis, and Chiesi. DL has received grant support, honoraria and consultancy fees from GSK. SPB is supported by NIH grant K23HL133438. He has served on advisory boards for Sunovion and GlaxoSmithKline. CH reports grants from National Institutes of Health, during the conduct of the study; personal fees from AstraZeneca, personal fees from Concert Pharmaceuticals, personal fees from 23andMe, grants from Novartis, grants from Boehringer-Ingelheim, outside the submitted work. EKS received grants and travel support from GlaxoSmithKline within the past three years. MLM reports grants from NIH, other from Parker B. Francis Foundation, during the conduct of the study; personal fees from Pfizer, outside the submitted work. RTS reports personal fees from GlaxoSmithKline, during the conduct of the study. MTD reports grants from NIH, American Lung Association, Department of Defense, and the Department of Veterans Affairs; personal fees from AstraZeneca, Boehringer Ingelheim, PneumRx/BTG, Mereo, Quark Pharmaceuticals and GSK, and contracted clinical trial support from Boehringer Ingelheim, Novartis, AstraZeneca, Yungjin, PneumRx/BTG, Pulmonx, Boston Scientific, Gala, Nuvaira, and GSK. PJC has received research support and consulting fees from GSK and Novartis. JMW reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NCATS, grants from Bayer, grants and other from GSK, other from Boehringer Ingelheim, grants and other from Mereo BioPharma, other from PRA, outside the submitted work; .

Figures

Fig. 1
Fig. 1
Volcano plot of differential gene expression of cachectic vs. non-cachectic COPD patients from COPDGene. The plot shows the log2 fold change on the x-axis and the unadjusted p-value on the y-axis (on the -log10 scale). Blue dots represent genes with a fold changed greater than or equal to + 1 and a p-value < 0.05
Fig. 2
Fig. 2
Summary of key findings in relationship to a putative role of iron in COPD cachexia. Genes in blue are significantly downregulated in COPD cachexia in manuscript analyses
See this image and copyright information in PMC

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