Natsuko Taniguchi

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis.

BackgroundMannose receptor (MR) is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition and thought to be critical in shaping host immune response. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with sarcoidosis.MethodsNine single nucleotide polymorphisms (SNPs), encompassing the MRC1 gene, were genotyped in a total of 605 Japanese consisting of 181 sarcoidosis patients and 424 healthy controls.ResultsSuggestive evidence of association between rs691005 SNP and risk of sarcoidosis was observed independent of sex and age in a recessive model (P = 0.001).ConclusionsThese results suggest that MRC1 is an important candidate gene for sarcoidosis. This is the first study to imply that genetic variants in MRC1, a major member of the C-type lectin, contribute to the development of sarcoidosis.

The CC16 A38G polymorphism is associated with asymptomatic airway hyper-responsiveness and development of late-onset asthma.

BACKGROUND Clara cell secretory protein (CC16) is expressed primarily in the respiratory tract and is a potent anti-inflammatory agent that protects the airway from inflammation. The associations of the A38G polymorphism in this gene with asymptomatic airway hyper-responsiveness (AHR), which is considered a risk factor for future asthma in adults, and the development of adult-onset asthma are unclear. OBJECTIVE To evaluate the association of the CC16 A38G polymorphism with asymptomatic AHR in healthy young adults and the development of adult-onset asthma and the association between plasma CC16 level according to this genotype and asymptomatic AHR. METHODS Nonspecific AHR was measured in 154 asymptomatic, young, healthy adults using a continuous methacholine inhalation method. The cumulative dose values of inhaled methacholine measured at the inflection point at which respiratory conductance started to decrease (Dmin) were used as an index of AHR. Case-control analysis was performed for the association between this polymorphism and the development of asthma in 1,086 unrelated Japanese subjects (504 subjects with asthma and 582 healthy subjects). RESULTS The 38AA + AG genotype was associated with lower Dmin values and lower plasma CC16 levels (P = .012 and .020). There was a significant positive correlation between Dmin values and plasma CC16 levels (P = .012). In the case-control study, the 38AA + AG genotype was significantly associated with late-onset asthma (onset at >40 years; odds ratio, 1.63; P = .016). CONCLUSION These results suggest that the CC16 A38G polymorphism may play a role in asymptomatic AHR and contribute to the development of late-onset asthma.

Sinus Computed Tomographic Findings in Adult Smokers and Nonsmokers with Asthma. Analysis of Clinical Indices and Biomarkers

Rationale: When they occur together, sinusitis and asthma are often thought to represent anatomically separate components of the same chronic inflammatory airway disease. Information about the effect of smoking on the interaction between sinusitis and asthma in patients who have both disorders is limited. Objectives: To evaluate the effect of cigarette smoking on the relationship between the presence and severity of sinusitis and selected asthma‐related indices in adults who have asthma. Methods: This study included 127 patients with severe asthma and 79 patients with mild to moderate asthma. Clinical data were obtained from all subjects during a 2‐day stay at Hokkaido University Hospital (Sapporo, Japan). The Lund‐Mackay scoring system was used to assess the anatomic extent and severity of sinusitis as revealed by sinus computed tomographic (CT) images obtained during hospitalization. We examined associations between Lund‐Mackay scores and a variety of asthma‐related indices and levels of biomarkers in blood and sputum. To clarify the effect of smoking on these associations, we conducted separate analyses for nonsmoking (<10 pack‐years; n = 130) and smoking subjects (≥10 pack‐years; n = 76). Measurements and Main Results: In our cohort of adults with asthma, we found significant positive relationships between the presence and severity of sinusitis as assessed by Lund‐Mackay score and the severity of asthma as measured by percent predicted FEV1 or FEV1/FVC for nonsmoking subjects (<10 pack‐years) but not for cigarette smokers (>10 pack‐years). Lund‐Mackay scores correlated with blood and sputum eosinophil counts, serum IgE levels, and fractional exhaled nitric oxide, regardless of smoking status. Lund‐Mackay scores also showed significant positive associations with serum periostin and chemokine C‐C motif ligand 18 levels, regardless of smoking status, whereas a positive association with plasma osteopontin level was seen only for nonsmoking subjects. Conclusions: We found an association between the severity of sinusitis on CT imaging and the severity of concomitant asthma on spirometry for nonsmoking adults but not for smokers. In adults with asthma, CT imaging evidence of severe sinusitis indicates intense Th2‐related inflammation, regardless of smoking status.

Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma

RATIONALE Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers. METHODS We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. MEASUREMENTS AND MAIN RESULTS Five clinical clusters were identified, including two characterized by high pack-year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later. CONCLUSIONS This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254).

Distinct Phenotypes of Smokers with Fixed Airflow Limitation Identified by Cluster Analysis of Severe Asthma

Rationale: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. Objectives: To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma. Methods: We recruited a total of 127 subjects with severe asthma, including 59 current or ex‐smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Clinical variables obtained during a 2‐day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. Results: Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later. Conclusions: This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma.

Prospective predictors of exacerbation status in severe asthma over a 3-year follow-up

A predisposition to exacerbations is being recognized as a distinct phenotype with “previous exacerbations” representing the strongest clinical factor associated with future exacerbation. Thus, to identify additional novel biomarkers associated with asthma exacerbations, “past exacerbation status” must be included as a confounding factor.