Effect of Common Medications on Longitudinal Pectoralis Muscle Area in Smokers.

Background: Cigarette smoke contributes to skeletal muscle wasting. While exercise and nutritional therapies are effective in improving skeletal muscle quantity and quality, the effect of medications on longitudinal muscle loss is unclear. We investigated whether long-term use of common medications affects longitudinal skeletal muscle changes in current and former smokers.

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies.

Background: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets.

Osteoarthritis Across Joint Sites in the Million Veteran Program Cohort: Insights From Electronic Health Records and Military Service History.

Objective: To characterize the relationship between the frequency of idiopathic osteoarthritis (OA) and characteristics including demographics, comorbidities, military service history, and physical health in a veteran population.

Methods: We performed a cohort study in the Million Veteran Program (MVP) using International Classification of Diseases, 9th and 10th revision codes to define the frequency of site-specific OA across 3 joints or unspecified OA in veterans with respect to demographics (eg, age, sex, race and ethnicity), military service data, detailed electronic health records, military branch, and war era.

Results: We validated previous reports of sex- and age-dependent differences in OA frequency, and we identified that unspecified OA was associated with a higher frequency of 16 Deyo-Charlson comorbidities.

Proteomics and machine learning in the prediction and explanation of low pectoralis muscle area.

Low muscle mass is associated with numerous adverse outcomes independent of other associated comorbid diseases. We aimed to predict and understand an individual's risk for developing low muscle mass using proteomics and machine learning. We identified eight biomarkers associated with low pectoralis muscle area (PMA).

Association of with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study ( = 6144 participants of European ancestry and = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group).

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes.

Rationale: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear.

Objectives: Define high-risk COPD subtypes using both genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximizing differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets.

Examining the Effect of Genes on Depression as Mediated by Smoking and Modified by Sex.

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components).

Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease due to loss-of-function mutations in the gene. DMD-related skeletal muscle wasting is typified by an aberrant immune response involving upregulation of TGFβ family of cytokines. We previously demonstrated that bone morphogenetic protein 4 (BMP4) is increased in DMD and BMP4 stimulation induces a 20-fold upregulation of transcription.

Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease.

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.

Proteomics and Machine Learning in the Prediction and Explanation of Low Pectoralis Muscle Area.

Low muscle mass is associated with numerous adverse outcomes independent of other associated comorbid diseases. We aimed to predict and understand an individual's risk for developing low muscle mass using proteomics and machine learning. We identified 8 biomarkers associated with low pectoralis muscle area (PMA).

Genetically Predicted Body Mass Index and Mortality in Chronic Obstructive Pulmonary Disease.

Body mass index (BMI) is associated with chronic obstructive pulmonary disease (COPD) mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate the causal mechanisms and predict risk. To examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD.

Association of musculoskeletal involvement with lung function and mortality in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with high mortality. Low muscle mass, frailty and sarcopenia lead to functional impairment that negatively impact quality of life and survival but are not used in clinical practice. We aimed to determine the association of Fat-free mass index (FFMI) and frailty with lung function, exercise tolerance and survival in patients with IPF.

Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease.

Background: Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age-related) sarcopenia.

Associations Between Muscle Weakness and Clinical Outcomes in Current and Former Smokers.

Introduction: Smokers with chronic obstructive pulmonary disease (COPD) are at increased risk of muscle weakness. There are limited data describing weakness in smokers with normal spirometry and preserved ratio-impaired spirometry (PRISm), 2 subgroups at risk of respiratory symptom burden and activity limitations. In this study, we evaluated the associations of 2 weakness measures, sit-to-stand (STS) and handgrip strength (HGS), with clinical outcomes in smokers with COPD, normal spirometry, and PRISm.

Update on the Etiology, Assessment, and Management of COPD Cachexia: Considerations for the Clinician.

Cachexia is a commonly observed but frequently neglected extra-pulmonary manifestation in patients with chronic obstructive pulmonary disease (COPD). Cachexia is a multifactorial syndrome characterized by severe loss of body weight, muscle, and fat, as well as increased protein catabolism. COPD cachexia places a high burden on patients (eg, increased mortality risk and disease burden, reduced exercise capacity and quality of life) and the healthcare system (eg, increased number, length, and cost of hospitalizations).

Novel genetic loci associated with osteoarthritis in multi-ancestry analyses in the Million Veteran Program and UK Biobank.

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.

Increased chest CT derived bone and muscle measures capture markers of improved morbidity and mortality in COPD.

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.

Comparative transcriptomics in human COPD reveals dysregulated genes uniquely expressed in ferrets.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with poor treatment options. However, most mouse models of COPD produce a primarily emphysematous disease not recapitulating clinically meaningful COPD features like chronic bronchitis.

Methods: Wild-type ferrets (Mustela putorius furo) were divided randomly into two groups: whole body cigarette smoke exposure and air controls.

Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program.

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic research, including data harmonization, analysis, and reporting.

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity.