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1.
Respir Res ; 23(1): 311, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36376854

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging and is associated with comorbid conditions including osteoporosis and sarcopenia. These extrapulmonary conditions are highly prevalent yet frequently underdiagnosed and overlooked by pulmonologists in COPD treatment and management. There is evidence supporting a role for bone-muscle crosstalk which may compound osteoporosis and sarcopenia risk in COPD. Chest CT is commonly utilized in COPD management, and we evaluated its utility to identify low bone mineral density (BMD) and reduced pectoralis muscle area (PMA) as surrogates for osteoporosis and sarcopenia. We then tested whether BMD and PMA were associated with morbidity and mortality in COPD. METHODS: BMD and PMA were analyzed from chest CT scans of 8468 COPDGene participants with COPD and controls (smoking and non-smoking). Multivariable regression models tested the relationship of BMD and PMA with measures of function (6-min walk distance (6MWD), handgrip strength) and disease severity (percent emphysema and lung function). Multivariable Cox proportional hazards models were used to evaluate the relationship between sex-specific quartiles of BMD and/or PMA derived from non-smoking controls with all-cause mortality. RESULTS: COPD subjects had significantly lower BMD and PMA compared with controls. Higher BMD and PMA were associated with increased physical function and less disease severity. Participants with the highest BMD and PMA quartiles had a significantly reduced mortality risk (36% and 46%) compared to the lowest quartiles. CONCLUSIONS: These findings highlight the potential for CT-derived BMD and PMA to characterize osteoporosis and sarcopenia using equipment available in the pulmonary setting.


Assuntos
Osteoporose , Doença Pulmonar Obstrutiva Crônica , Sarcopenia , Humanos , Masculino , Feminino , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Força da Mão , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Osteoporose/complicações , Tomografia Computadorizada por Raios X/efeitos adversos , Morbidade , Músculos , Densidade Óssea
2.
Respir Res ; 21(1): 100, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32354332

RESUMO

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.


Assuntos
Caquexia/genética , Caquexia/metabolismo , Heme/genética , Heme/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Idoso de 80 Anos ou mais , Caquexia/epidemiologia , Estudos de Coortes , Regulação para Baixo/fisiologia , Feminino , Seguimentos , Estudo de Associação Genômica Ampla/métodos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia
4.
J Cachexia Sarcopenia Muscle ; 15(3): 1016-1029, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38649783

RESUMO

BACKGROUND: Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. METHODS: Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. RESULTS: Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. CONCLUSIONS: Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Transcriptoma , Perfilação da Expressão Gênica
5.
Sci Rep ; 12(1): 3080, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35197532

RESUMO

Fibrosis is a leading cause of morbidity and mortality worldwide. Although fibrosis may involve different organ systems, transforming growth factor-ß (TGFß) has been established as a master regulator of fibrosis across organs. Pirfenidone and Nintedanib are the only currently-approved drugs to treat fibrosis, specifically idiopathic pulmonary fibrosis, but their mechanisms of action remain poorly understood. To identify novel drug targets and uncover potential mechanisms by which these drugs attenuate fibrosis, we performed an integrative 'omics analysis of transcriptomic and proteomic responses to TGFß1-stimulated lung fibroblasts. Significant findings were annotated as associated with pirfenidone and nintedanib treatment in silico via Coremine. Integrative 'omics identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFß1 treatment that was enriched (FDR-p = 0.04) with genes associated with pirfenidone and nintedanib treatment. While a subset of genes in this module have been implicated in fibrogenesis, several novel TGFß1 signaling targets were identified. Specifically, four genes (BASP1, HSD17B6, CDH11, and TNS1) have been associated with pirfenidone, while five genes (CLINT1, CADM1, MTDH, SYDE1, and MCTS1) have been associated with nintedanib, and MYDGF has been implicated with treatment using both drugs. Using the Clue Drug Repurposing Hub, succinic acid was highlighted as a metabolite regulated by the protein encoded by HSD17B6. This study provides new insights into the anti-fibrotic actions of pirfenidone and nintedanib and identifies novel targets for future mechanistic studies.


Assuntos
Antifibróticos/farmacologia , Biologia Computacional/métodos , Proteínas da Matriz Extracelular/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Indóis/farmacologia , Piridonas/farmacologia , Fator de Crescimento Transformador beta/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antifibróticos/uso terapêutico , Caderinas/genética , Caderinas/metabolismo , Molécula 1 de Adesão Celular/genética , Molécula 1 de Adesão Celular/metabolismo , Feminino , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Piridonas/uso terapêutico , Racemases e Epimerases/genética , Racemases e Epimerases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Tensinas/genética , Tensinas/metabolismo
6.
Nat Genet ; 54(12): 1816-1826, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36411363

RESUMO

Osteoarthritis is a common progressive joint disease. As no effective medical interventions are available, osteoarthritis often progresses to the end stage, in which only surgical options such as total joint replacement are available. A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached. To date, there have been no large multiancestry genetic studies of osteoarthritis. Here, we leveraged the unique resources of 484,374 participants in the Million Veteran Program and UK Biobank to address this gap. Analyses included participants of European, African, Asian and Hispanic descent. We discovered osteoarthritis-associated genetic variation at 10 loci and replicated findings from previous osteoarthritis studies. We also present evidence that some osteoarthritis-associated regions are robust to population ancestry. Drug repurposing analyses revealed enrichment of targets of several medication classes and provide potential insight into the etiology of beneficial effects of antiepileptics on osteoarthritis pain.


Assuntos
Bancos de Espécimes Biológicos , Loci Gênicos , Humanos , Reino Unido
7.
J Cachexia Sarcopenia Muscle ; 12(6): 1803-1817, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34523824

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach. METHODS: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m2 ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data. RESULTS: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10-8 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling. CONCLUSIONS: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.


Assuntos
Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica , Adulto , Teorema de Bayes , Variação Genética , Humanos , Músculo Esquelético , Proteínas do Tecido Nervoso , Doença Pulmonar Obstrutiva Crônica/genética , Regeneração , Redução de Peso/genética
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