CC16: A Treatable Trait in Asthma?
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ABSTRACT:
SUBMITTER: Bloom CI
PROVIDER: S-EPMC10563192 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
Publications
CC16: A Treatable Trait in Asthma?
Bloom Chloe I CI Adcock Ian M IM
American journal of respiratory and critical care medicine 20231001 7
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Project description:The astounding number of genetic variants revealed in the 15 years of genome-wide association studies of asthma has not kept pace with the goals of translational genomics. Moving asthma diagnosis from a nonspecific umbrella term to specific phenotypes/endotypes and related traits may provide insights into features that may be prevented or alleviated by therapeutical intervention. This review provides an overview of the different asthma endotypes and phenotypes and the genomic findings from asthma studies using patient stratification strategies and asthma-related traits. Asthma genomic research for treatable traits has uncovered novel and previously reported asthma loci, primarily through studies in Europeans. Novel genomic findings for asthma phenotypes and related traits may arise from multi-trait and specific phenotyping strategies in diverse populations.
| S-EPMC10531302 | biostudies-literature
Project description:BackgroundThe club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects and is a potential early biomarker of lung damage. The CC16 single nucleotide polymorphism (SNP) rs3741240 risk allele (A) has been inconsistently linked to asthma; other tagging SNPs in the gene have not been explored. The aim was to determine whether CC16 tagging polymorphisms are associated with adult asthma, asthma subtypes or asthma control in the Agricultural Lung Health Study (ALHS).MethodsThe ALHS is an asthma case-control study nested in the Agricultural Health Study cohort. Asthma cases were individuals with current doctor diagnosed asthma, likely undiagnosed asthma, or asthma-COPD overlap defined by questionnaire. We also examined asthma subtypes and asthma control. Five CC16 tagging SNPs were imputed to 1000 Genomes Integrated phase 1 reference panel. Logistic regression was used to estimate associations between CC16 SNPs and asthma outcomes adjusted for covariates.ResultsThe sample included 1120 asthma cases and 1926 controls of European ancestry, with a mean age of 63 years. The frequency of the risk genotype (AA) for rs3741240 was 12.5% (n = 382). CC16 rs3741240 was not associated with adult asthma outcomes. A tagging SNP in the CC16 gene, rs12270961 was associated with uncontrolled asthma (n = 208, ORadj= 1.4, 95% CI 1.0, 1.9; p = 0.03).ConclusionThis study, the largest study to investigate associations between CC16 tagging SNPs and asthma phenotypes in adults, did not confirm an association of rs3741240 with adult asthma. A tagging SNP in CC16 suggests a potential relationship with asthma control.
| S-EPMC9644514 | biostudies-literature
Project description:IntroductionClub cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures.MethodsCirculating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures.ResultsBMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001).ConclusionsWe demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.
| S-EPMC9241210 | biostudies-literature
Project description:Rationale: CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Objectives: Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Methods: Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Measurements and Main Results: Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC) and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Conclusions: Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.
| S-EPMC9940145 | biostudies-literature
Project description:Traditional stepwise approach usually adjusts the treatment regimen based on changes in asthma symptoms and severity to achieve good asthma control. However, due to the generalized heterogeneity and complexity of asthma, its therapeutic efficacy in difficult-to-treat asthma is limited. Recently, a precision medicine approach based on the identification and intervention of treatable traits of chronic airway disease has been proposed and appears to be of greater benefit to asthmatics. We reported a 71-year-old male with uncontrolled asthma and multiple exacerbations over the past year. He complained of persistent dyspnea despite high-dose of inhaled corticosteroids plus other controllers. Does this patient have some potential treatable traits contributing to difficult-to-treat asthma? Through a multidimensional assessment of three domains including pulmonary, extrapulmonary, and behavioral/risk factors, 15 treatable traits were identified in the patient, mainly including airflow limitation, eosinophilic airway inflammation, small airway dysfunction, exacerbation prone, dilated cardiomyopathy, diabetes mellitus, inhaler device polypharmacy, smoking, and the absence of an asthma action plan. After targeted treatment for these treatable traits, the patient experienced significant improvement in dyspnea and he could maintain good asthma control with low-dose inhaled corticosteroids and long-acting β2-agonist. This study shows that, in response to the limitation of a stepwise approach to therapy, treatable traits is a new strategy where patients are individually assessed for a specified set of treatable problems, and an individualized treatment program is developed and implemented based on this multidimensional assessment, especially for difficult-to-treat asthma.
| S-EPMC10037422 | biostudies-literature
Project description: Not available
| S-EPMC6587719 | biostudies-literature
Project description:Low Club Cell 16 kDa protein (CC16) plasma levels are linked to accelerated lung function decline in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke-exposed (CS-exposed) Cc16-/- mice have exaggerated COPD-like disease associated with increased NF-κB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16-/- mice and whether increased NF-κB activation contributes to the exaggerated COPD in CS-exposed Cc16-/- lungs. CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 (rhCC16) or an NF-κB inhibitor versus vehicle beginning at the midpoint of the exposures. COPD-like disease and NF-κB activation were measured in the lungs. RhCC16 limited the progression of emphysema, small airway fibrosis, and chronic bronchitis-like disease in WT and Cc16-/- mice partly by reducing pulmonary inflammation (reducing myeloid leukocytes and/or increasing regulatory T and/or B cells) and alveolar septal cell apoptosis, reducing NF-κB activation in CS-exposed Cc16-/- lungs, and rescuing the reduced Foxj1 expression in CS-exposed Cc16-/- lungs. IMD0354 treatment reduced exaggerated lung inflammation and rescued the reduced Foxj1 expression in CS-exposed Cc16-/- mice. RhCC16 treatment reduced NF-κB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16-/- mice partly by inhibiting NF-κB activation and represents a potentially novel therapeutic approach for COPD.
| S-EPMC10070105 | biostudies-literature
Project description:Current management of chronic cough is largely based on sequential therapeutic trials. The concept of treatable traits was first introduced for individualized treatment of chronic airway diseases; however, it has emerged as a potentially useful strategy in revising the management of chronic cough. This narrative review aimed to analyze the literature to determine if fractional exhaled nitric oxide (FeNO) is a treatable trait in chronic cough, compared to other type 2 biomarkers, and to summarize current knowledge and gaps in the clinical application. An online electronic search was performed on PubMed, Web of Science, and Scopus of English-language literature with following keywords: cough, nitric oxide (NO), eosinophils, biomarker, and treatable trait. Relevance and eligibility of each article were assessed by one or more of the authors and a narrative review was composed. Eosinophilic or type 2 airway inflammation is a major treatable trait in patients with chronic cough. Induced sputum tests are regarded as the gold standard for defining inflammatory phenotype, however, technically demanding and cannot be widely applied in clinical practice. FeNO, a practical biomarker, has emerged as an alternative to induced sputum analyses. Mechanistic and clinical evidence indicated that FeNO had a potential for diagnostic utility and treatment response predictability. FeNO measurement may help to identify patients with chronic cough that will benefit from corticosteroid treatment. Further studies are warranted to determine the diagnostic roles of FeNO in the management of patients with chronic cough.
| S-EPMC10636432 | biostudies-literature
Project description:Cutibacterium acnes (C. acnes, formerly Propionibacterium acnes) is considered to be a non-pathogenic resident of the human skin, as well as mucosal surfaces. However, it also has been demonstrated that C. acnes plays a pathogenic role in diseases such as acne vulgaris or implant infections after orthopedic surgery. Besides a role in infectious disease, this bacterium also seems to harbor immunomodulatory effects demonstrated by studies using C. acnes to enhance anti-tumor activity in various cancers or vaccination response. Sarcoidosis is a systemic inflammatory disorder of unknown causes. Cultures of C. acnes in biopsy samples of sarcoidosis patients, its presence in BAL fluid, tissue samples as well as antibodies against this bacterium found in serum of patients with sarcoidosis suggest an etiological role in this disease. In this review we address the antigenic as well as immunomodulatory potential of C. acnes with a focus on sarcoidosis. Furthermore, a potential role for antibiotic treatment in patients with sarcoidosis will be explored.
| S-EPMC9415339 | biostudies-literature
Project description:BackgroundRespiratory multimorbidities are linked to asthma, such as allergic rhinitis (AR) with early allergic asthma and chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) with late nonallergic asthma.ObjectiveOur aim was to investigate the association of asthma severity and control with specific upper airway phenotypes.MethodPatients with asthma were prospectively recruited from 23 pulmonology and ear, nose, and throat clinics. Asthma severity and control, as well as upper airway comorbidities (AR and non-AR [NAR], CRSwNP, and CRS without nasal polyps [CRSsNP]) were assessed according to international consensus guidelines definitions.ResultsA total of 492 asthmatic patients were included. Half of the asthmatic patients (49.6%) had associated rhinitis (37.0% had AR and 12.6% had NAR) and 36.2% had CRS (16.7% had CRSsNP and 19.5% had CRSwNP), whereas 14.2% had no sinonasal symptoms. Most cases of AR (78%) and NAR (84%) were present in patients with mild-to-moderate asthma, whereas CRSwNP was more frequent in patients with severe asthma (35% [P < .001]), mainly nonatopic asthma (44% [P < .001]). Patients with severe asthma with CRSwNP had worse asthma control, which was correlated (r = 0.249 [P = .034]) with sinus occupancy. Multiple logistic regression analysis showed that late-onset asthma, intolerance of aspirin and/or nonsteroidal anti-inflammatory drugs, and CRSwNP were independently associated with severe asthma.ConclusionSevere asthma is associated with CRSwNP, with sinus occupancy affecting asthma control. This study has identified 2 main different upper airway treatable traits, AR and CRSwNP, which need further evaluation to improve management and control of patients with asthma.
| S-EPMC10510007 | biostudies-literature