Heme metabolism genes Downregulated in COPD Cachexia

Wilson, A.C.; Kumar, Preeti Lakshman; Lee, Sool; Parker, Margaret M.; Arora, Itika; Morrow, Jarrett; Wouters, Emiel F.M.; Casaburi, Richard; Rennard, Stephen I.; Lomas, David A.; Agustí, Àlvar; Tal‐Singer, Ruth; Wells, James M.; Bhatt, Surya P.; Washko, George R.; Thannickal, Victor J.; Tiwari, Hemant K.; Hersh, Craig P.; Castaldi, Peter J.; Silverman, Edwin K.; McDonald, Merry-Lynn

doi:10.1186/s12931-020-01336-w

Cited by 4 publications

(3 citation statements)

References 39 publications

(57 reference statements)

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“…Most of the transcriptomic and proteomic associations with emphysema in our study were sensitive to the adjustment for BMI, suggesting that BMI may be involved in the causal pathways underlying these associations. According to a recent study, COPD patients’ cachexia may be influenced by impaired heme biosynthesis, which leads to excess iron accumulation and oxidative tissue damage (74). Interestingly, the PPIX metabolic pathway, which is directly involved in heme biosynthesis (75), and iron ion homeostasis were enriched in our top 250 most mediated genes.…”

Section: Discussionmentioning

confidence: 99%

Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

Suryadevara

Gregory

et al. 2022

Preprint

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Rationale: Emphysema is a key component of COPD with important prognostic implications. Identifying blood-based biomarkers of emphysema will facilitate early diagnosis and possible development of targeted therapies. Objectives: Discover blood transcriptomic and proteomic biomarkers for chest computed tomography-quantified emphysema in smokers and develop predictive biomarker panels. Methods: Emphysema blood biomarker discovery was performed using differential gene expression, alternative splicing, and protein association analyses in a training set of 2,370 COPDGene participants with available whole blood RNA sequencing, plasma SomaScan proteomics, and clinical data. Validation was conducted in a testing set of 1,016 COPDGene subjects. Since body mass index (BMI) and emphysema often co-occur, we performed a mediation analysis to quantify the effect of BMI on gene and protein associations with emphysema. Predictive models were also developed using elastic net to predict quantitative emphysema from cell blood count, RNA sequencing, and proteomic biomarkers. Model accuracy was assessed by area under the receiver-operator-characteristic-curves (AUROC) for subjects stratified into tertiles of emphysema severity. Measurements and Main Results: 4,913 genes, 1,478 isoforms, 386 exons, and 881 proteins were significantly associated with emphysema (FDR 10%). 75% and 77% of genes and proteins, respectively, were mediated by BMI. The significantly enriched biological pathways were involved in inflammation and cell differentiation, differing between the most and least BMI-mediated genes. The cell blood count plus protein model achieved the highest performance with an AUROC of 0.89. Conclusions: Blood transcriptome and proteome-wide analyses reveal key biological pathways of emphysema and enhance the prediction of emphysema.

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Section: Discussionmentioning

confidence: 99%

Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

Suryadevara

Gregory

et al. 2022

Preprint

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“…In COPD cachectic patients, replicated genes that regulate heme metabolism were downregulated in blood samples [ 19 ], while mitochondrial breakdown signaling increased in the vastus lateralis muscle [ 20 ]. These findings were directly associated with both disease severity and the loss of mitochondrial content.…”

Section: Introductionmentioning

confidence: 99%

Iron Depletion in Systemic and Muscle Compartments Defines a Specific Phenotype of Severe COPD in Female and Male Patients: Implications in Exercise Tolerance

et al. 2022

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We hypothesized that iron content and regulatory factors, which may be involved in exercise tolerance, are differentially expressed in systemic and muscle compartments in iron deficient severe chronic obstructive pulmonary disease (COPD) patients. In the vastus lateralis and blood of severe COPD patients with/without iron depletion, iron content and regulators, exercise capacity, and muscle function were evaluated in 40 severe COPD patients: non-iron deficiency (NID) and iron deficiency (ID) (20 patients/group). In ID compared to NID patients, exercise capacity, muscle iron and ferritin content, serum transferrin saturation, hepcidin-25, and hemojuvelin decreased, while serum transferrin and soluble transferrin receptor and muscle IRP-1 and IRP-2 increased. Among all COPD, a significant positive correlation was detected between FEV1 and serum transferrin saturation. In ID patients, significant positive correlations were detected between serum ferritin, hepcidin, and muscle iron content and exercise tolerance and between muscle IRP-2 and serum ferritin and hepcidin levels. In ID severe COPD patients, iron content and its regulators are differentially expressed. A potential crosstalk between systemic and muscle compartments was observed in the ID patients. Lung function and exercise capacity were associated with several markers of iron metabolism regulation. Iron status should be included in the overall assessment of COPD patients given its implications in their exercise performance.

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“…Konishi et al concluded that existing international criteria, which focus on body composition and muscle mass loss, may underestimate cachexia in Asians because their physique differs from that of their Western counterparts 15 . Indeed, a study of predominantly Caucasian participants found that patients with advanced cancer had an average BMI of 25 kg/m 2 16,17 and patients with COPD around 27 kg/m 2 , 18 while a BMI of <20.7 kg/m 2 was reported in only 13.6% of patients with heart failure 19 . Asians have a lower BMI on average and a differential contribution of BMI to chronic diseases compared with Caucasians 20 .…”

Section: Introductionmentioning

confidence: 99%

Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia

Arai,

Maeda,

Wakabayashi

et al. 2023

J cachexia sarcopenia muscle

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Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three‐round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C‐reactive protein levels (>5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3–6 month period and suggested a tentative cut‐off value of 21 kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ‐5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient‐reported outcomes. The AWGC consensus offers a comprehensive definition and user‐friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co‐morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.

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Heme metabolism genes Downregulated in COPD Cachexia

Cited by 4 publications

References 39 publications

Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

Iron Depletion in Systemic and Muscle Compartments Defines a Specific Phenotype of Severe COPD in Female and Male Patients: Implications in Exercise Tolerance

Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia

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