Novel proteomics platforms, such as the aptamer‐based SOMAscan platform, can quantify large numbers of proteins efficiently and cost‐effectively and are rapidly growing in popularity. However, comparisons to conventional immunoassays remain underexplored, leaving investigators unsure when cross‐assay comparisons are appropriate. The correlation of results from immunoassays with relative protein quantification is explored by SOMAscan. For 63 proteins assessed in two chronic obstructive pulmonary disease (COPD) cohorts, subpopulations and intermediate outcome measures in COPD Study (SPIROMICS), and COPDGene, using myriad rules based medicine multiplex immunoassays and SOMAscan, Spearman correlation coefficients range from −0.13 to 0.97, with a median correlation coefficient of ≈0.5 and consistent results across cohorts. A similar range is observed for immunoassays in the population‐based Multi‐Ethnic Study of Atherosclerosis and for other assays in COPDGene and SPIROMICS. Comparisons of relative quantification from the antibody‐based Olink platform and SOMAscan in a small cohort of myocardial infarction patients also show a wide correlation range. Finally, cis pQTL data, mass spectrometry aptamer confirmation, and other publicly available data are integrated to assess relationships with observed correlations. Correlation between proteomics assays shows a wide range and should be carefully considered when comparing and meta‐analyzing proteomics data across assays and studies.
Smoking causes chronic obstructive pulmonary disease (COPD). Though recent studies identified a COPD metabolomic signature in blood, no large studies examine the metabolome in bronchoalveolar lavage (BAL) fluid, a more direct representation of lung cell metabolism. We performed untargeted liquid chromatography–mass spectrometry (LC–MS) on BAL and matched plasma from 115 subjects from the SPIROMICS cohort. Regression was performed with COPD phenotypes as the outcome and metabolites as the predictor, adjusted for clinical covariates and false discovery rate. Weighted gene co-expression network analysis (WGCNA) grouped metabolites into modules which were then associated with phenotypes. K-means clustering grouped similar subjects. We detected 7939 and 10,561 compounds in BAL and paired plasma samples, respectively. FEV1/FVC (Forced Expiratory Volume in One Second/Forced Vital Capacity) ratio, emphysema, FEV1 % predicted, and COPD exacerbations associated with 1230, 792, eight, and one BAL compounds, respectively. Only two plasma compounds associated with a COPD phenotype (emphysema). Three BAL co-expression modules associated with FEV1/FVC and emphysema. K-means BAL metabolomic signature clustering identified two groups, one with more airway obstruction (34% of subjects, median FEV1/FVC 0.67), one with less (66% of subjects, median FEV1/FVC 0.77; p < 2 × 10−4). Associations between metabolites and COPD phenotypes are more robustly represented in BAL compared to plasma.
Chronic obstructive pulmonary disease (COPD) is a disease in which airflow obstruction in the lung makes it difficult for patients to breathe. Although COPD occurs predominantly in smokers, there are still deficits in our understanding of the additional risk factors in smokers. To gain a deeper understanding of the COPD molecular signatures, we used Sparse Multiple Canonical Correlation Network (SmCCNet), a recently developed tool that uses sparse multiple canonical correlation analysis, to integrate proteomic and metabolomic data from the blood of 1008 participants of the COPDGene study to identify novel protein–metabolite networks associated with lung function and emphysema. Our aim was to integrate -omic data through SmCCNet to build interpretable networks that could assist in the discovery of novel biomarkers that may have been overlooked in alternative biomarker discovery methods. We found a protein–metabolite network consisting of 13 proteins and 7 metabolites which had a −0.34 correlation (p-value = 2.5 × 10−28) to lung function. We also found a network of 13 proteins and 10 metabolites that had a −0.27 correlation (p-value = 2.6 × 10−17) to percent emphysema. Protein–metabolite networks can provide additional information on the progression of COPD that complements single biomarker or single -omic analyses.
Background Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. Methods sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). Results Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. Conclusions Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
Background: Small studies have recently suggested that there are specific plasma metabolic signatures in chronic obstructive pulmonary disease (COPD), but there have been no large comprehensive study of metabolomic signatures in COPD that also integrate genetic variants. Materials and Methods: Fresh frozen plasma from 957 non-Hispanic white subjects in COPDGene was used to quantify 995 metabolites with Metabolon's global metabolomics platform. Metabolite associations with five COPD phenotypes (chronic bronchitis, exacerbation frequency, percent emphysema, post-bronchodilator forced expiratory volume at one second [FEV 1 ]/forced vital capacity [FVC], and FEV 1 percent predicted) were assessed. A metabolome-wide association study was performed to find genetic associations with metabolite levels. Significantly associated single-nucleotide polymorphisms were tested for replication with independent metabolomic platforms and independent cohorts. COPD phenotype-driven modules were identified in network analysis integrated with genetic associations to assess gene-metabolite-phenotype interactions. Results: Of metabolites tested, 147 (14.8%) were significantly associated with at least 1 COPD phenotype. Associations with airflow obstruction were enriched for diacylglycerols and branched chain amino acids. Genetic associations were observed with 109 (11%) metabolites, 72 (66%) of which replicated in an independent cohort. For 20 metabolites, more than 20% of variance was explained by genetics. A sparse network of COPD phenotype-driven modules was identified, often containing metabolites missed in previous testing. Of the 26 COPD phenotype-driven modules, 6 contained metabolites with significant met-QTLs, although little module variance was explained by genetics. Conclusion: A dysregulation of systemic metabolism was predominantly found in COPD phenotypes characterized by airflow obstruction, where we identified robust heritable effects on individual metabolite abundances. However, network analysis, which increased the statistical power to detect associations missed previously in classic regression analyses, revealed that the genetic influence on COPD phenotype-driven metabolomic modules was modest when compared with clinical and environmental factors.
Susceptibility and progression of lung disease, as well as response to treatment, often differ by sex, yet the metabolic mechanisms driving these sex-specific differences are still poorly understood. Women with chronic obstructive pulmonary disease (COPD) have less emphysema and more small airway disease on average than men, though these differences become less pronounced with more severe airflow limitation. While small studies of targeted metabolites have identified compounds differing by sex and COPD status, the sex-specific effect of COPD on systemic metabolism has yet to be interrogated. Significant sex differences were observed in 9 of the 11 modules identified in COPDGene. Sex-specific associations by COPD status and emphysema were observed in 3 modules for each phenotype. Sex stratified individual metabolite associations with COPD demonstrated male-specific associations in sphingomyelins and female-specific associations in acyl carnitines and phosphatidylethanolamines. There was high preservation of module assignments in SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) and similar female-specific shift in acyl carnitines. Several COPD associated metabolites differed by sex. Acyl carnitines and sphingomyelins demonstrate sex-specific abundances and may represent important metabolic signatures of sex differences in COPD. Accurately characterizing the sex-specific molecular differences in COPD is vital for personalized diagnostics and therapeutics.
Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of mortality in the United States; however, COPD has heterogeneous clinical phenotypes. This is the first large scale attempt which uses transcriptomics, proteomics, and metabolomics (multi-omics) to determine whether there are molecularly defined clusters with distinct clinical phenotypes that may underlie the clinical heterogeneity. Subjects included 3,278 subjects from the COPDGene cohort with at least one of the following profiles: whole blood transcriptomes (2,650 subjects); plasma proteomes (1,013 subjects); and plasma metabolomes (1,136 subjects). 489 subjects had all three contemporaneous -omics profiles. Autoencoder embeddings were performed individually for each -omics dataset. Embeddings underwent subspace clustering using MineClus, either individually by -omics or combined, followed by recursive feature selection based on Support Vector Machines. Clusters were tested for associations with clinical variables. Optimal single -omics clustering typically resulted in two clusters. Although there was overlap for individual -omics cluster membership, each -omics cluster tended to be defined by unique molecular pathways. For example, prominent molecular features of the metabolome-based clustering included sphingomyelin, while key molecular features of the transcriptome-based clusters were related to immune and bacterial responses. We also found that when we integrated the -omics data at a later stage, we identified subtypes that varied based on age, severity of disease, in addition to diffusing capacity of the lungs for carbon monoxide, and precent on atrial fibrillation. In contrast, when we integrated the -omics data at an earlier stage by treating all data sets equally, there were no clinical differences between subtypes. Similar to clinical clustering, which has revealed multiple heterogenous clinical phenotypes, we show that transcriptomics, proteomics, and metabolomics tend to define clusters of COPD patients with different clinical characteristics. Thus, integrating these different -omics data sets affords additional insight into the molecular nature of COPD and its heterogeneity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.