Abstract
IntroductionCachexia 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.MethodsWe 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.ResultsThe 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).DiscussionSeveral 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.
Highlights
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
Phenotype data In COPDGene, cachexia was defined at visit two, approximately five years from baseline, as either self-reported, unintentional weight loss greater than 5% in the past year or low body mass index (BMI) (< 20 kg/m2) in addition to one of three criteria: low 6MWD (< 350 m; a surrogate for decreased muscle strength), anemia or low fat-free mass index (FFMI) (FFMI < 15 kg/m2 among women and FFMI < 17 kg/m2 among men)
In this study, we identified novel gene expression signatures associated with COPD cachexia in two independent cohorts of participants with moderate to severe COPD
Summary
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. Previous studies of gene expression changes in COPD cachexia have had small sample sizes, non-disease controls for comparison, employed a candidate-gene approach, or have focused on proxies for cachexia such as low fat-free mass index (FFMI) [3, 4]. These studies have highlighted interesting genes with relevant biology to cachexia such as FOXO1 and FOXO3 [5]. Low FFMI and low BMI are components of the multifactorial definition of cachexia, these measures alone are not sufficient to monitor cachexia in the entire population at risk [7]
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