Genetically Predicted Body Mass Index and Mortality in COPD.

RATIONALE: BMI is associated with COPD mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate causal mechanisms and predict risk. OBJECTIVES: To examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD. METHODS: We developed a polygenic score for BMI (PGSBMI) and tested for associations of the PGSBMI with all-cause, respiratory, and cardiovascular mortality in participants with COPD from the COPDGene, ECLIPSE, and Framingham Heart studies. We calculated the difference between measured BMI and PGS-predicted BMI (BMIdiff) and categorized participants into groups of discordantly low (BMIdiff < 20th percentile), concordant (BMIdiff between 20th - 80th percentile), and discordantly high (BMIdiff > 80th percentile) BMI. We applied Cox models, examined potential non-linear associations of the PGSBMI and BMIdiff with mortality, and summarized results with meta-analysis. MEASUREMENTS AND MAIN RESULTS: We observed significant non-linear associations of measured BMI and BMIdiff, but not PGSBMI, with all-cause mortality. In meta-analyses, a one standard deviation increase in the PGSBMI was associated with an increased hazard for cardiovascular mortality (HR=1.29, 95% CI=1.12-1.49), but not with respiratory or all-cause mortality. Compared to participants with concordant measured and genetically predicted BMI, those with discordantly low BMI had higher mortality risk for all-cause (HR=1.57, CI=1.41-1.74) and respiratory death (HR=2.01, CI=1.61-2.51). CONCLUSIONS: In people with COPD, higher genetically predicted BMI is associated with higher cardiovascular mortality but not respiratory mortality. Individuals with discordantly low BMI have higher all-cause and respiratory mortality compared to those with concordant BMI.

Atrial arrhythmia related outcomes in critically ill COVID-19 patients.

RATIONALE: Coronavirus disease 2019 (COVID-19) is associated with many clinical manifestations including respiratory failure and cardiovascular compromise. OBJECTIVES: We examine outcomes in critically ill individuals with COVID-19 who develop atrial tachyarrhythmias. METHODS: We collected data from electrocardiograms and the electronic medical record of COVID-19 positive (COVID+ ) and negative (COVID- ) individuals admitted to our medical intensive care unit between February 29 and June 28, 2020. We compared clinical and demographic characteristics, new onset atrial tachyarrhythmia, hemodynamic compromise following atrial tachyarrhythmia, and in-hospital mortality in COVID+ versus COVID- . Hemodynamic compromise was defined as having a new or increased vasopressor requirement or the need for direct current cardioversion for hemodynamic instability within 1 hour of atrial tachyarrhythmia onset. RESULTS: Of 300 individuals included, 200 were COVID+ and 100 were COVID- . Mean age was 60 ± 16 years, 180 (60%) were males, and 170 (57%) were African American. New onset atrial tachyarrhythmia occurred in 16% of COVID+ and 19% of COVID- individuals (P = .51). When compared to COVID- participants without atrial tachyarrhythmia, COVID+ individuals with new onset atrial tachyarrhythmia had higher mortality after multivariable adjustment (OR 5.0, 95% CI 1.9-13.5). New onset atrial tachyarrhythmia was followed by hemodynamic compromise in 18 COVID+ but no COVID- participants (P = .0001). COVID+ individuals with hemodynamic compromise after atrial tachyarrhythmia required increased ventilatory support at the time of atrial tachyarrhythmia onset. CONCLUSIONS: Atrial tachyarrhythmia is associated with increased mortality in critically ill individuals with COVID-19, especially those mechanically ventilated. Recognition of this could assist with clinical care for individuals with COVID-19.

Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia.

The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.

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). We built 3 random forest classification models that used either clinical measures, feature selected biomarkers, or both to predict development of low PMA. The area under the receiver operating characteristic curve for each model was: clinical-only = 0.646, biomarker-only = 0.740, and combined = 0.744. We displayed the heterogenetic nature of an individual's risk for developing low PMA and identified 2 distinct subtypes of participants who developed low PMA. While additional validation is required, our methods for identifying and understanding individual and group risk for low muscle mass could be used to enable developments in the personalized prevention of low muscle mass.

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. 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.

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. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups. Measurements and Main Results: We examined two high-risk omics-defined groups in non-overlapping test sets (n=1,133 NHW COPDGene, n=299 African American (AA) COPDGene, n=468 ECLIPSE). We defined "High activity" (low PRS/high TRS) and "severe risk" (high PRS/high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signaling processes compared to a low-risk (low PRS, low TRS) reference subgroup. "High activity" but not "severe risk" participants had greater prospective FEV 1 decline (COPDGene: -51 mL/year; ECLIPSE: - 40 mL/year) and their proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors. Conclusions: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.

Letter to the Editor: "Use of inhaled epoprostenol with high flow nasal oxygen in non-intubated patients with severe COVID-19".

PURPOSE: Acute lung injury associated with COVID-19 contributes significantly to its morbidity and mortality. Though invasive mechanical ventilation is sometimes necessary, the use of high flow nasal oxygen may avoid the need for mechanical ventilation in some patients. For patients approaching the limits of high flow nasal oxygen support, addition of inhaled pulmonary vasodilators is becoming more common but little is known about its effects. This is the first descriptive study of a cohort of patients receiving inhaled epoprostenol with high flow nasal oxygen for COVID-19. MATERIALS AND METHODS: We collected clinical data from the first fifty patients to receive inhaled epoprostenol while on high flow nasal oxygen at our institution. We compared the characteristics of patients who did and did not respond to epoprostenol addition. RESULTS: The 18 patients that did not stabilize or improve following initiation of inhaled epoprostenol had similar rates of invasive mechanical ventilation as those who improved or stabilized (50% vs 56%). Rates of mortality were not significantly different between the two groups (17% and 31%). CONCLUSIONS: In patients with COVID-19 induced hypoxemic respiratory failure, the use of inhaled epoprostenol with high flow nasal oxygen is feasible, but physiologic signs of response were not related to clinical outcomes.

Integrated bioinformatics analysis identifies established and novel TGFß1-regulated genes modulated by anti-fibrotic drugs.

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.

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). The etiology of COPD cachexia involves a complex interplay of non-modifiable and modifiable factors (eg, smoking, hypoxemia, hypercapnia, physical inactivity, energy imbalance, and exacerbations). Addressing these modifiable factors is needed to prevent and treat COPD cachexia. Oral nutritional supplementation combined with exercise training should be the primary multimodal treatment approach. Adding a pharmacological agent might be considered in some, but not all, patients with COPD cachexia. Clinicians and researchers should use longitudinal measures (eg, weight loss, muscle mass loss) instead of cross-sectional measures (eg, low body mass index or fat-free mass index) where possible to evaluate patients with COPD cachexia. Lastly, in future research, more detailed phenotyping of cachectic patients to enable a better comparison of included patients between studies, prospective longitudinal studies, and more focus on the impact of exacerbations and the role of biomarkers in COPD cachexia, are highly recommended.

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. 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.

Levodopa response reveals sepiapterin reductase deficiency in a female heterozygote with adrenoleukodystrophy.

We report a 4-year-old girl heterozygous for X-linked adrenoleukodystrophy (ALD) who displayed dopa-responsive motor symptoms and was subsequently diagnosed with sepiapterin reductase deficiency (SPR; OMIM 182125). Her father and paternal uncle had known ALD, and she was found to have elevated plasma very long chain fatty acids and a mutation in the ABCD1 gene. She had language delay, severe hypotonia and abnormal eye movements and responded dramatically to a trial of levodopa (4 mg/kg per day). Two mutations within the gene for sepiapterin reductase were found and cultured skin fibroblasts demonstrated near zero activity of the enzyme. This case illustrates the importance of treatment trials that may give rise to biochemical clues to the underlying diagnosis, and the need to continue to search for diagnoses despite a misleading family history.