Fibrinogen: A Feasible Biomarker in Identifying the Severity and Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Background Chronic obstructive pulmonary disease (COPD) is no longer considered a disease exclusive to the respiratory system. It is a multipronged disease with both lung and systemic involvement. Although the forced expiratory volume (FEV) in one second is one of the most commonly used markers to assess disease severity, in recent years, biomarkers such as interleukin-1 beta, serum C-X-C motif chemokine ligand 10, fibrinogen, soluble receptor for advanced glycation, surfactant protein D, and club cell secretory protein have been proven to be effective markers to assess disease severity. Objective The current study aimed to test the association of fibrinogen levels with increased exacerbation of COPD per year and lower lung function and to discuss its potential utility as a biomarker. Methodology A total of 105 participants were enrolled in the study. The study participants included 35 stable COPD patients, 35 COPD patients with acute exacerbation, and 35 non-COPD healthy controls (matched for age and gender). All patients above 18 years of age who were diagnosed with COPD as per the Global Initiative for Chronic Obstructive Disease (GOLD) guidelines were considered for inclusion in the study. The patients were divided into stable COPD group and acute exacerbations of COPD (AECOPD) group based on the Anthonisen criteria. Sociodemographic factors, six-minute walk test, Medical Research Council Dyspnea Scale, and COPD Assessment Test scale were computed. Spirometry according to the American Thoracic Society guidelines and hematological investigations including serum fibrinogen were performed. Additionally, GOLD staging and severity indices were used to determine the clinical phenotyping of COPD, namely, ADO (age, dyspnea, airflow obstruction) index, BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, and DOSE (dyspnea, obstruction, smoking, exacerbation) index. Results Plasma fibrinogen level was significantly higher in the COPD groups compared to the control group. Plasma fibrinogen level was elevated in AECOPD compared to stable COPD patients. In addition, fibrinogen levels showed a positive correlation with important functional indices and prognostic markers such as BODE, ADO, and DOSE indices and a negative correlation with lung function. The odds of predicting an acute exacerbation of COPD for patients with FEV of <50% and FEV of >50% were 17.2 (area under the curve [AUC] = 0.825; sensitivity = 90.4%; specificity = 62.79%) and 15.1 (AUC = 0.791; sensitivity = 57.7%; specificity = 92.5%), respectively. Conclusions Plasma fibrinogen has the potential to be an important biomarker in the management of COPD and its exacerbation due to its ability to be responsive to the COPD disease statuses such as the severity of COPD and AECOPD.

Distinct asthma phenotypes with low maximal attainment of lung function on cluster analysis.

OBJECTIVE: Asthma is a heterogeneous disease with varying clinical presentations, severity and ability to achieve asthma control. The present study aimed to characterize clinical phenotypes of asthma in an Indian cohort of subjects using a cluster analysis approach. METHODS: Patients with confirmed asthma (N = 100) and at least 6-months of follow-up data, identified by retrospective chart review, were included in this study. Demographics, age at disease onset, disease duration, body mass index, serial spirometry and allergen sensitization were assessed. Asthma control was assessed prospectively using Global Initiative for Asthma and Asthma Control Test. R version 3.4.3 was used for statistical analysis. Ward's minimum-variance hierarchical clustering method was performed using an agglomerative (bottom-up) approach. To compare differences between clusters, analysis of variance using Kruskal-Wallis test (continuous variables) and chi-square test (categorical variables) was used. RESULTS: Cluster analysis of 100 treatment-naive patients with asthma identified four clusters. Cluster 1, (N = 40), childhood onset of disease, normal body weight, equal gender distribution and achieved normal lung function. Cluster 2 (N = 16) included adolescent disease-onset, obese, majority males and had poor attainment of maximum lung functions. Cluster 3 (N = 20) were older, late-onset of disease, obese, majority male and had poor attainment of maximum lung function. Cluster 4 (N = 24) had adult-onset of disease, obese, predominantly female and achieved normal lung function. CONCLUSIONS: In an Indian cohort of well-characterized patients with asthma, cluster analysis identified four distinct clinical phenotypes of asthma, two of which had poor attainment of maximum lung functions.

Haplotype analysis of ADAM33 polymorphisms in asthma: A pilot study.

Background & objectives: ADAM33 is implicated as a potentially strong candidate gene for asthma and bronchial hyper-responsiveness. Many polymorphisms of ADAM33 have been studied along with ADAM33 expression in various cells of the lungs. Haplotype analysis also showed association with asthma in different populations across the world. Therefore, the aim of this study was to perform a comprehensive screening of ADAM33 polymorphisms in adult patients with asthma. Methods: Thirty five polymorphisms of ADAM33 were genotyped in 55 patients with asthma and 53 controls. The association of single nucleotide polymorphisms (SNPs) and haplotypes with phenotypes of asthma was analysed. Results: The genotype, minor allele frequency, odds ratio and Hardy-Weinberg equilibrium did not show any significant difference among cases and controls. No association was found between SNPs of ADAM33 with the severity of asthma. Correlation analysis of ADAM33 SNPs to the phenotypes, based on clinical variables and allergen sensitization, did not show significant difference. Haplotype analysis showed that rs2280090 and rs2280091 were associated with asthma in the patient group. Interpretation & conclusions: Haplotype analysis showed an association of the two SNP variations with asthma. These SNPs lead to amino acid change and are prone to phosphorylation, which may affect expression levels and protein function of ADAM33 and asthma susceptibility.

Copy number variation burden on asthma subgenome in normal cohorts identifies susceptibility markers.

PURPOSE: Asthma is a complex disease caused by interplay of genes and environment on the genome of an individual. Copy number variations (CNVs) are more common compared to the other variations that disrupt genome organization. The effect of CNVs on asthma subgenome has been less studied compared to studies on the other variations. We report the assessments of CNV burden in asthma genes of normal cohorts carried out in different geographical areas of the world and discuss the relevance of the observation with respect to asthma pathogenesis. METHODS: CNV analysis was performed using Affymerix high-resolution arrays, and various bioinformatics tools were used to understand the influence of genes on asthma pathogenesis. RESULTS: This study identified 61 genes associated with asthma and provided various mechanisms and pathways underlying asthma pathogenesis. CCL3L1, ADAM8, and MUC5B were the most prevalent asthma genes. Among them, CCL3L1 was found across all 12 populations in varying copy number states. This study also identified the inheritance of asthma-CNVs from parents to offspring creating the latent period for manifestation of asthma. CONCLUSIONS: This study revealed CNV burden with varying copy number states and identified susceptibility towards the disease manifestation. It can be hypothesized that primary CNVs may not be the initiating event in the pathogenesis of asthma and additional preceding mutations or CNVs may be required. The initiator or primary CNVs sensitize normal cohorts leading to an increased probability of accumulating mutations or exposure to allergic stimulating agents that can augment the development of asthma.

Molecular interaction network and pathway studies of ADAM33 potentially relevant to asthma.

BACKGROUND: Asthma is a complex disease caused by gene-gene, gene-protein, and protein-protein interactions and the influence of environment, which plays a significant role in causing asthma pathogenesis. ADAM33 is known to be an important gene involved in asthma pathogenesis. No one single gene is a causal factor of asthma; rather, asthma is caused by a complex interaction of multiple genes having pathogenetic and protective effects. OBJECTIVE: To identify and understand the interacting genes and proteins of ADAM33. METHODS: The Ingenuity Pathway Analysis and GeneMANIA tools and a literature survey were used to identify the interacting candidates of ADAM33 and the WEB-based GEne SeT AnaLysis Toolkit was used to perform enrichment analysis of the proteins identified. RESULTS: Keeping ADAM33 as a major hub, the authors identified some proteins whose interaction with ADAM33 had been associated with asthma and they recognized some proteins, such as amyloid ß (A4) precursor protein, ataxin-7, α4-integrin, α5-integrin, α9-integrin, tissue inhibitor of metalloproteinase-4, and ubiquilin-4, that had not been previously associated with asthma. CONCLUSION: The proteins identified in this study were enriched for various mechanisms that are involved in airway hyperresponsiveness, and through the interaction with ADAM33, they may have potential relevance in asthma.

An understanding of the genetic basis of asthma.

Asthma is the most common chronic childhood disease in developed nations and its prevalence has increased in the world over the last 25 years. It is a complex disease with both genetic and environmental risk factors. Asthma is caused by multiple interacting genes, some having a protective effect and others contributing to the disease pathogenesis, with each gene having its own tendency to be influenced by the environment. This article reviews the current state of the genetics of asthma in six categories, viz. epidemiology, management, aetiology, family and twin studies, segregation and linkage studies, and candidate genes and single nucleotide polymorphisms (SNPs).

Effect of animal contact and microbial exposures on the prevalence of atopy and asthma in urban vs rural children in India.

BACKGROUND: Environmental factors, including microbial exposures and close animal contact, are implicated in the lower prevalence of asthma and allergy in rural vs urban children. OBJECTIVES: To determine (1) the prevalence of asthma, rhinitis, eczema, and atopic sensitization in rural and urban children in India; (2) differences in microbial and animal exposures in these locales; and (3) whether differences in environmental exposures account for the different rates of asthma and atopy in these locales. METHODS: One child from each of 50 urban (Mysore) and 50 rural (Vinobha) households in southern India was randomly selected for data analysis. Allergy, asthma, health, environment, and lifestyle information was obtained using a questionnaire and household inspections. Atopy was determined via skin prick testing for common allergens. Endotoxin content was measured in house dust samples. RESULTS: Children from rural vs urban areas had lower prevalences of self-reported asthma (8% vs 30%; P = .005), rhinitis (22% vs 42%; P = .03), and atopic sensitization (36% vs 58%; P = .03). Higher median dust endotoxin loads were found in rural vs urban households (6.50 x 10(4) EU/m2 vs 1.27 x 10(4) EU/m2; P < .001). In multivariate analysis, close indoor animal contact (adjusted odds ratio [OR] 0.2; 90% confidence interval [CI], 0.05-0.9), outdoor animal contact (OR, 0.3; 90% CI, 0.1-0.8), and exclusive breastfeeding for at least 6 months (OR, 0.2; 90% CI, 0.1-0.5) were associated with lower atopic sensitization; mud flooring was associated with lower self-reported wheezing (OR, 0.1; 90% CI, 0.02-1.0). CONCLUSION: Children in India who live with close animal contact and mud flooring and who were exclusively breastfed in infancy are less likely to develop asthma, rhinitis, and atopic sensitization.