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.
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Authors | Ava C Wilson, Preeti L Kumar, Sool Lee, Margaret M Parker, Itika Arora, Jarrett D Morrow, Emiel F M Wouters, Richard Casaburi, Stephen I Rennard, David A Lomas, Alvar Agusti, Ruth Tal-Singer, Mark T Dransfield, J Michael Wells, Surya P Bhatt, George Washko, Victor J Thannickal, Hemant K Tiwari, Craig P Hersh, Peter J Castaldi, Edwin K Silverman, Merry-Lynn N McDonald |
Journal | Respiratory research
(Respir Res)
Vol. 21
Issue 1
Pg. 100
(May 01 2020)
ISSN: 1465-993X [Electronic] England |
PMID | 32354332
(Publication Type: Journal Article, Observational Study)
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Chemical References |
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Topics |
- Aged
- Aged, 80 and over
- Cachexia
(epidemiology, genetics, metabolism)
- Cohort Studies
- Down-Regulation
(physiology)
- Female
- Follow-Up Studies
- Genome-Wide Association Study
(methods)
- Heme
(genetics, metabolism)
- Humans
- Longitudinal Studies
- Male
- Middle Aged
- Pulmonary Disease, Chronic Obstructive
(epidemiology, genetics, metabolism)
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