Genetic association of the functional CDHR3 genotype with early-onset adult asthma in Japanese populations

Kanazawa, Jun; Masuko, Hironori; Yatagai, Yohei; Sakamoto, Tohru; Kaneko, Yoshiko; Kitazawa, Haruna; Iijima, Hiroaki; Naito, Takashi; Saito, Takefumi; Noguchi, Emiko; Konno, Satoshi; Nishimura, Masaharu; Hirota, Tomomitsu; Tamari, Mayumi; Hizawa, Nobuyuki

doi:10.1016/j.alit.2017.02.012

Cited by 28 publications

(23 citation statements)

References 30 publications

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“…This extends a growing body of data implicating the rs6967330 variant in the risk of asthma exacerbations/hospitalization and related traits, including early-life bronchiolitis, earlyonset asthma, and chronic rhinosinusitis. [16][17][18][19]29 Monitoring of gene and protein expression throughout AEC differentiation indicated robust CDHR3 expression before the appearance of cilia. Our finding of CDHR3 localization near the basal bodies in ciliating and mature ciliated cells raised the possibility of its involvement in ciliogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Several genetic studies have now associated the rs6967330 SNP with risk of asthma-related illnesses, including in Danish and Japanese patient cohorts. [16][17][18][19] Despite these findings, many questions remain, including (1) whether lung cells other than ciliated cells express CDHR3; (2) whether, as a cadherin-like protein, CDHR3 plays a role in cell adhesion or other ciliated cell functions; (3) whether perturbation of CDHR3 expression in human airway epithelial cells (AECs) modulates HRV-C infection levels; (4) whether the rs6967330 variant of CDHR3 modifies HRV-C infection in AECs; and (5) whether rs6967330 or other cis-variants function as CDHR3 expression quantitative trait loci (eQTLs) and modify risk for childhood asthma exacerbations. Here we use CDHR3 CRISPR-Cas9-edited and CDHR3 risk genotype-specific primary AECs for functional experiments, as well as a comprehensive CDHR3 nasal airway epithelial eQTL analysis and genetic association analysis for CDHR3 functional variants with childhood asthma exacerbations, to answer these questions.…”

Section: Abstract: Airway Epithelium Crispr Rhinovirus Expressionmentioning

confidence: 99%

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Functional genomics of CDHR3 confirms its role in HRV-C infection and childhood asthma exacerbations

Everman

Sajuthi

Saef

et al. 2019

Journal of Allergy and Clinical Immunology

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CDHR3 + Ciliated Cells Role of CDHR3 in HRV-C15 infection of differentiated primary airway epithelium Coding variant association with CDHR3 gene expression, HRV-C15 infection, and asthma hospitalization CDHR3 CRISPR Knockout Cells CDHR3 rs6967330 [GG] CDHR3 rs6967330 [AA] CDHR3 HRV-C15 Infection HRV-C15 Infection HRV-C15 Infection CDHR3 gene expression CDHR3 gene expression HRV-C15 Infection Asthma-induced hospitalization in minority children CDHR3 Abbreviations CDHR3: Cadherin-related family member 3; HRV-C15: Human Rhinovirus species C15 and childhood asthma exacerbations Background: Research in transformed immortalized cell lines indicates the cadherin-related family member 3 (CDHR3) protein serves as a receptor for human rhinovirus (HRV)-C. Similar experiments indicate that the CDHR3 coding variant rs6967330 increases CDHR3 protein surface expression. Objective: We sought to determine whether CDHR3 is necessary for HRV-C infection of primary airway epithelial cells (AECs) and to identify molecular mechanisms by which CDHR3 variants confer risk for asthma exacerbations. Methods: CDHR3 function and influence on HRV-C infection were investigated by using single-cell transcriptomics, CRISPR-Cas9 gene knockout, and genotype-specific donor experiments performed in primary AECs. Nasal airway epithelium cisexpression quantitative trait locus (eQTL) analysis of CDHR3 From a the Center for Genes,

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Section: Discussionmentioning

confidence: 99%

Section: Abstract: Airway Epithelium Crispr Rhinovirus Expressionmentioning

confidence: 99%

Functional genomics of CDHR3 confirms its role in HRV-C infection and childhood asthma exacerbations

Everman

Sajuthi

Saef

et al. 2019

Journal of Allergy and Clinical Immunology

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“…RV-C was first identified in 2006 and associated with high symptom burdens in children and asthmatics 26,27 . Recently, an asthma-related cadherin-related family member 3 (CDHR3) gene variant 28 was associated with greater RV-C receptor display on pulmonary cell surfaces of children and adults, and associated with higher susceptibility to severe virus-triggered asthma episodes 29,30 . In line, Romero-Espinoza et al detected predominantly RV-C in children with acute asthma exacerbations by mNGS 31 .…”

Section: Discussionmentioning

confidence: 99%

The respiratory virome and exacerbations in patients with chronic obstructive pulmonary disease

Rijn

Boheemen

Carbo

et al. 2019

Preprint

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Introduction: Exacerbations are major contributors to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), and respiratory bacterial and viral infections are an important trigger for the occurrence of such exacerbations. However, using conventional diagnostic techniques, a causative agent is not always found. Metagenomic next-generation sequencing (mNGS) allows analysis of the complete virome, but has not yet been applied in COPD exacerbations. Objectives: To study the respiratory virome in nasopharyngeal samples during COPD exacerbations using mNGS. Study design: 88 nasopharyngeal swabs from 63 patients from the Bergen COPD Exacerbation Study (2006-2010) were analysed by mNGS and in-house qPCR for respiratory viruses. Both DNA and RNA were sequenced simultaneously using an Illumina library preparation protocol with in-house adaptations. Results: By mNGS, 23/88 samples tested positive. Sensitivity and specificity were both 96% for diagnostic targets (23/24 and 1067/1120, respectively). Viral pathogens only detected by mNGS were herpes simplex virus type 1 and coronavirus OC43. A positive correlation was found between Cq value and mNGS viral species reads (p=0.008). Patients with viral pathogens had lower percentages of bacteriophages (p<0.000). No correlation was found between viral reads (species and genus level) and clinical markers. Conclusions: The mNGS protocol used was highly sensitive and specific for semi-quantitative detection of respiratory viruses. Excellent negative predictive value implicates the power of mNGS to exclude any infectious cause in one test, with consequences for clinical decision making. Reduced abundance of bacteriophages in COPD patients with viral pathogens implicates skewing of the virome, and speculatively the bacterial population, during infection.

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“…[15][16][17][18][19] Cadherin-related family member 3 (a receptor for RV-C) and atopy have been shown to be risk factors for the development of early-onset asthma. 20 Cadherin-related family member 3 mediates RV-C binding and replication in airway epithelia, and polymorphism in gene encoding the protein has been linked with increased susceptibility to asthma. 21,22 We aimed to study whether RSV or RV types are differently associated with the use of long-term asthma control medication during the 4 years after severe bronchiolitis during infancy.…”

Section: Introductionmentioning

confidence: 99%

Rhinovirus Type in Severe Bronchiolitis and the Development of Asthma

Bergroth

Aakula

Elenius

et al. 2020

The Journal of Allergy and Clinical Immunology: In Practice

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What is already known about this topic? Respiratory syncytial virus (RSV)-and rhinovirus (RV)-induced bronchiolitis are associated with an increased risk of asthma.What does this article add to our knowledge? Compared with children with RSV-induced bronchiolitis, children with RV-Ae or RV-Ceinduced bronchiolitis start asthma control medication earlier and are more likely to use it 4 years later. The risk is especially high among patients with RV-C, atopic dermatitis, and fever.How does this study impact current management guidelines? Secondary prevention strategies targeting rhinoviruses, especially RV-C, might help to prevent childhood asthma.BACKGROUND: Respiratory syncytial virus (RSV)-and rhinovirus (RV)-induced bronchiolitis are associated with an increased risk of asthma, but more detailed information is needed on virus types. OBJECTIVE: To study whether RSV or RV types are differentially associated with the future use of asthma control medication. METHODS: Over 2 consecutive winter seasons (2008-2010), we enrolled 408 children hospitalized for bronchiolitis at age less than 24 months into a prospective, 3-center, 4-year follow-up study in Finland. Virus detection was performed by real-time reverse transcription PCR from nasal wash samples. Four years later, we examined current use of asthma control medication. RESULTS: A total of 349 (86%) children completed the 4-year follow-up. At study entry, the median age was 7.5 months, and 42% had RSV, 29% RV, 2% both RSV and RV, and 27% non-RSV/-RV etiology. The children with RV-A (adjusted hazard ratio, 2.3; P [ .01), RV-C (adjusted hazard ratio, 3.5; P < .001), and non-RSV/-RV (adjusted hazard ratio, 2.0; P [ .004) bronchiolitis started the asthma control medication earlier than did children with RSV bronchiolitis. Four years later, 27% of patients used asthma control medication; both RV-A (adjusted odds ratio, 3.0; P [ .03) and RV-C (adjusted odds ratio, 3.7; P < .001) etiology were associated with the current use of asthma medication. The highest risk was found among patients with RV-C, atopic dermatitis, and fever (adjusted odds ratio, 5.0; P [ .03). CONCLUSIONS: Severe bronchiolitis caused by RV-A and RV-C was associated with earlier initiation and prolonged use of asthma control medication. The risk was especially high when bronchiolitis was associated with RV-C, atopic dermatitis, and fever. Ó

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Genetic association of the functional CDHR3 genotype with early-onset adult asthma in Japanese populations

Cited by 28 publications

References 30 publications

Functional genomics of CDHR3 confirms its role in HRV-C infection and childhood asthma exacerbations

Functional genomics of CDHR3 confirms its role in HRV-C infection and childhood asthma exacerbations

The respiratory virome and exacerbations in patients with chronic obstructive pulmonary disease

Rhinovirus Type in Severe Bronchiolitis and the Development of Asthma

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