Lower FEV1 in non-COPD, nonasthmatic subjects: association with smoking, annual decline in FEV1, total IgE levels, and TSLP genotypes

Few studies have investigated the significance of decreased FEV1 in non-COPD, nonasthmatic healthy subjects. We hypothesized that a lower FEV1 in these subjects is a potential marker of an increased susceptibility to obstructive lung disease such as asthma and COPD. This was a cross-sectional analysis of 1505 Japanese adults. We divided the population of healthy adults with no respiratory diseases whose FEV1/FVC ratio was ≥70% (n = 1369) into 2 groups according to their prebronchodilator FEV1 (% predicted) measurements: <80% (n = 217) and ≥80% (n = 1152). We compared clinical data – including gender, age, smoking habits, total IgE levels, and annual decline of FEV1 – between these 2 groups. In addition, as our group recently found that TSLP variants are associated with asthma and reduced lung function, we assessed whether TSLP single nucleotide polymorphisms (SNPs) were associated with baseline lung function in non-COPD, nonasthmatic healthy subjects (n = 1368). Although about half of the subjects with lower FEV1 had never smoked, smoking was the main risk factor for the decreased FEV1 in non-COPD, nonasthmatic subjects. However, the subjects with lower FEV1 had a significantly higher annual decline in FEV1 independent of smoking status. Airflow obstruction was associated with increased levels of total serum IgE (P = 0.029) and with 2 functional TSLP SNPs (corrected P = 0.027–0.058 for FEV1% predicted, corrected P = 0.015–0.033 for FEV1/FVC). This study highlights the importance of early recognition of a decreased FEV1 in healthy subjects without evident pulmonary diseases because it predicts a rapid decline in FEV1 irrespective of smoking status. Our series of studies identified TSLP variants as a potential susceptibility locus to asthma and to lower lung function in non-COPD, nonasthmatic healthy subjects, which may support the contention that genetic determinants of lung function influence susceptibility to asthma

〔研究ノート〕 グリーンナッツオイルの摂取は マウスのDHAおよびEPAを増加させるか

In general, it has been recognized that n-3 fatty acids have the effect of suppressing inflammation and deterioration of cognitive ability. In addition, it is reported that a-linolenic acid is partially converted into DHA and EPA in the human body. On the other hand, like linseed oil and perilla oil, green nut oil （GNO） is rich in a-linolenic acid, one of the n-3 fatty acids, but not enough research on green nut oil has been done yet.Therefore, using mice, we investigated the effects of green nut oil intake on fatty acid composition in the liver, erythrocyte membrane, and brain. The result suggested that a-linolenic acid in green nut oil increases DHA and EPA in the bodies of mice. While mice that ingested corn oil （as a contrast） showed a slight decrease in brain DHA in 20-week-old mice as compared with 8-week-old mice, mice that ingested green nut oil showed no significant difference between 8 and 20-week-olds

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

BackgroundRecent studies have demonstrated that a coding SNP (rs6967330, Cys529→Tyr) in cadherin-related family member 3 (CDHR3), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of this variant to the development of adult asthma.MethodsWe performed a candidate gene case–control association study of 2 independent Japanese populations (a total of 3366 adults). The odds ratios (ORs) for association of the A allele at rs6967330 with adult asthma were calculated according to age at onset of asthma. In addition, the effect of the CDHR3 genotype on the development of specific asthma phenotypes was examined.ResultsThe A allele was associated with asthma (OR = 1.56; Mantel–Haenszel p = 0.0040) when the analysis was limited to patients with early-onset adult asthma. In addition, when the analysis was limited to atopic individuals, a stronger association of the CDHR3 variant with early-onset asthma was found, and interaction of the CDHR3 genotype with atopy was demonstrated. Finally, a significant association of this variant was specifically found with a phenotype of asthma characterized by atopy, early-onset, and lower lung function.ConclusionsOur study supports the concept that the CDHR3 variant is an important susceptibility factor for severe adult asthma in individuals who develop the disease in early life. The interaction between the CDHR3 variant and atopy indicates that genetic predisposition to early respiratory viral infection is combined with atopy in promoting asthma

Experience of Mothers of Hikikomori Children during their High School and University Days : The Process of Mother’s Participation in a Hikikomori “Parents’ Group”

The goal of this study is to clarify the experience process up to joining a parents' group, for mothers of school refusal children who refused to go to school or university and ended up as hikikomori, refusing to go out at all. Another goal is to examine support for such mothers. Semistructured interviews were conducted with twelve mothers. By analyzing the interviews using the revised version of the grounded theory approach, five categories and twelve concepts were extracted. The central category was looking for a guidepost and this affected the other three categories. In (makeshift solution for child) mothers repeatedly tried to find some stopgap solution. In (anguish amid a sense of isolation) they struggled on alone, feeling isolated. In this process, mothers made the (decision to join a parents' group) because they wanted to meet someone who would understand, obtain useful information and have some idea of what the future might hold. Since the looking for a guidepost situation continued for some time before they made the (decision to join a parents' group) it is highly likely that these mothers' psychological state can be stabilized through an appropriate response, and that they will be able to deal with their child head on, and adopt an attitude which seeks to understand him. From the analysis results, it is suggested that “mother's acceptance” and “encouragement of supporter's understanding of hikikomori” are important elements in supporting responses to looking for a guidepost.本研究は、高校・大学時にひきこもった子どもの母親の、親の会に参加するまでの体験のプロ セスを明らかにし支援の検討を目的とした。母親12名を対象に半構造化面接を行い、面接内容を 修正版グラウンデッド・セオリー・アプローチを用いて分析した結果、５つのカテゴリーと12の 概念が抽出された。コアカテゴリーは≪探し求める道しるべ≫であり、その後の３つのカテゴ リーに影響を与えていた。〈子どもには対症療法〉でその場しのぎの対応を繰り返し〈孤独感の 中で苦悩〉し、わかる人とつながり有効な情報を得て先の展望を持ちたいという思いで〈親の会 への参加決断〉をしていた。≪探し求める道しるべ≫状態が継続していることから、ここへの適 切な対応で早期に母親の心理的安定を図ることができる可能性が高く、“母親の受容”、”支援 者のひきこもりに関する理解の促進”が重要な要素と考えられる

Role of Lung Function Genes in the Development of Asthma

Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 × 10−4) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction

An interaction between Nrf2 polymorphisms and smoking status affects annual decline in FEV1: a longitudinal retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>An Nrf2-dependent response is a central protective mechanism against oxidative stress. We propose that particular genetic variants of the <it>Nrf2 </it>gene may be associated with a rapid forced expiratory volume in one second (FEV₁) decline induced by cigarette smoking.</p> <p>Methods</p> <p>We conducted a retrospective cohort study of 915 Japanese from a general population. Values of annual decline in FEV₁were computed for each individual using a linear mixed-effect model. Multiple clinical characteristics were assessed to identify associations with annual FEV₁decline. Tag single-nucleotide polymorphisms (SNPs) in the <it>Nrf2 </it>gene (rs2001350, rs6726395, rs1962142, rs2364722) and one functional SNP (rs6721961) in the <it>Nrf2 </it>promoter region were genotyped to assess interactions between the <it>Nrf2 </it>polymorphisms and smoking status on annual FEV₁decline.</p> <p>Results</p> <p>Annual FEV₁decline was associated with smoking behavior and inversely correlated with FEV₁/FVC and FEV₁% predicted. The mean annual FEV₁declines in individuals with rs6726395 G/G, G/A, or A/A were 26.2, 22.3, and 20.8 mL/year, respectively, and differences in these means were statistically significant (p_corr= 0.016). We also found a significant interaction between rs6726395 genotype and smoking status on the FEV₁decline (p for interaction = 0.011). The haplotype rs2001350T/rs6726395A/rs1962142A/rs2364722A/rs6721961T was associated with lower annual decline in FEV₁(p = 0.004).</p> <p>Conclusions</p> <p>This study indicated that an Nrf2-dependent response to exogenous stimuli may affect annual FEV₁decline in the general population. It appears that the genetic influence of <it>Nrf2 </it>is modified by smoking status, suggesting the presence of a gene-environment interaction in accelerated decline in FEV₁.</p

Association analyses of eQTLs of the TYRO3 gene and allergic diseases in Japanese populations

BackgroundTYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations.MethodsWe performed a candidate gene case–control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations.ResultsA meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene–gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively.ConclusionsOur study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese

Genetic and Molecular Analysis of Wild-Derived Arrhythmic Mice

A new circadian variant was isolated by screening the intercross offspring of wild-caught mice (Mus musculus castaneus). This variant was characterized by an initial maintenance of damped oscillations and subsequent loss of rhythmicity after being transferred from light-dark (LD) cycles to constant darkness (DD). To map the genes responsible for the persistence of rhythmicity (circadian ratio) and the length of free-running period (τ), quantitative trait locus (QTL) analysis was performed using F2 mice obtained from an F1 cross between the circadian variant and C57BL/6J mice. As a result, a significant QTL with a main effect for circadian ratio (Arrhythmicity; Arrh-1) was mapped on Chromosome (Chr) 8. For τ, four significant QTLs, Short free-running period (Sfp-1) (Chr 1), Sfp-2 (Chr 6), Sfp-3 (Chr 8), Sfp-4 (Chr 11) were determined. An epistatic interaction was detected between Chr 3 (Arrh-2) and Chr 5 (Arrh-3). An in situ hybridization study of clock genes and mouse Period1::luciferase (mPer1::luc) real-time monitoring analysis in the suprachiasmatic nucleus (SCN) suggested that arrhythmicity in this variant might not be attributed to core circadian mechanisms in the SCN neurons. Our strategy using wild-derived variant mice may provide a novel opportunity to evaluate circadian and its related disorders in human that arise from the interaction between multiple variant genes