Ōsaka, Japan
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Tomita K.,University of Fukui | Sakashita M.,University of Fukui | Hirota T.,RIKEN | Tanaka S.,RIKEN | And 9 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2013

Background Allergic rhinitis (AR) is a very common disorder peaking in the teenage years that is mediated by hypersensitivity responses to environmental allergens. Although it is well established that the ORMDL3 locus at chromosome 17q21 is associated with susceptibility to bronchial asthma, the genetic influences of the polymorphisms of the locus in allergic rhinitis are unclear. Objective To examine whether the polymorphisms in the 17q21 asthma susceptibility locus are associated with allergic rhinitis in the Japanese population. Methods We performed linkage disequilibrium (LD) mapping of the locus using the HapMap database and conducted an association study of the locus with a total of 15 tag SNPs in two independent populations. We further evaluated correlations of genotypes with changes in expression of genes at the region in lymphoblastoid cell lines in the Japanese population and assessed the expression levels of the genes in nasal epithelium and various human tissues. Results We found a significant association between a total of five polymorphisms in the 17q21 asthma susceptibility locus, rs9303277, rs7216389, rs7224129, rs3744246, and rs4794820, and AR (minimum Pcombined = 0.00074, rs4794820). The expression level of the ORMDL3 transcript was significantly correlated with the genotype of rs12150079, rs7216389, rs3744246, and rs4794820 with P < 0.01 (minimum P = 0.0058, rs7216389), and ORMDL3 mRNA was highly expressed in nasal epithelium. Conclusion Genetic variants in the 17q21 asthma susceptibility locus are significantly associated with AR in the Japanese population. © 2012 John Wiley & Sons A/S.


Hirota T.,RIKEN | Takahashi A.,RIKEN | Kubo M.,RIKEN | Tsunoda T.,RIKEN | And 27 more authors.
Nature Genetics | Year: 2012

Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (P combined = 8.36 × 10-18), the major histocompatibility complex (MHC) region (P = 8.38 × 10-20), OR10A3-NLRP10 (P = 1.54 × 10-22), GLB1 (P = 2.77 × 10-16), CCDC80 (P = 1.56 × 10-19), CARD11 (P = 7.83 × 10-9), ZNF365 (P = 5.85 × 10-20) and CYP24A1-PFDN4 (P = 1.65 × 10-8). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis. © 2012 Nature America, Inc. All rights reserved.


Hirota T.,RIKEN | Saeki H.,Jikei University School of Medicine | Tomita K.,RIKEN | Tomita K.,University of Fukui | And 22 more authors.
PLoS ONE | Year: 2011

Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1 st population, 916 cases and 1,032 controls; 2 nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10 -6; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD. © 2011 Hirota et al.


Undarmaa S.,Chiba University | Mashimo Y.,Chiba University | Hattori S.,Chiba University | Shimojo N.,University of Shiga Prefecture | And 9 more authors.
Journal of Human Genetics | Year: 2010

In asthma genetics, the association of highly replicated susceptibility genes lacks consistency across populations. To identify genuine associations, we investigated the reproducibility of the 23 most promising asthma and asthma-related candidate genes in a moderately sized sample from the Japanese population. We compared the frequency of 33 polymorphisms in unrelated cases and controls and tested for their association with asthma, atopy and serum total IgE levels using allele frequency, codominant, dominant and recessive genotype models. On the basis of the consistency of our findings with previous meta-analyses and large replication studies, IL13, TNF, ADAM33, IL4RA and TBXA2R might represent common major asthma and asthma-related trait genes. Individual gene assessment was extended to the interactions between two polymorphisms using our original method. Interactions between TBXA2R and ADAM33, and IL4RA and C3 were suggested to increase the risk for childhood and all asthma (adult and childhood asthma combined). The confirmation of previously reported associations between gene polymorphisms and phenotypes was problematic when as few as several hundred samples per group were used. Stratification of the subjects by environmental factors or other confounding factors may be necessary to improve the sensitivity and reliability of association results. © 2010 The Japan Society of Human Genetics All rights reserved.


Otsuki M.,Osaka University | Miyatake A.,Miyatake Asthma Clinic | Fujita K.,University of Shiga Prefecture | Hamasaki T.,Osaka University | Kasayama S.,Osaka University
European Respiratory Journal | Year: 2010

Although inflammation is an important component of atherosclerosis, it is unknown whether inhaled corticosteroids (ICS) as anti-inflammatory drugs prevent atherosclerosis. In the present study, carotid atherosclerosis was evaluated by ultrasonography in 150 asthmatic patients who had been regularly treated with ICS, and in 150 matched nonasthmatic controls, with an assessment of atherosclerotic risk factors. Carotid intima-media thickness was significantly lower in the asthmatic patients than in the controls. The prevalence of carotid plaque tended to be lower in the asthmatic patients than in the controls. Defined carotid atherosclerosis was diagnosed in 51 of the asthmatic patients, who were older, with a higher prevalence of males, a higher prevalence of dyslipidaemia and a lower mean daily dose of ICS than the 99 patients without carotid atherosclerosis. Stepwise multiple logistic regression analysis identified age, male sex and dyslipidaemia as positive risk factors for carotid atherosclerosis. The mean daily dose of ICS was a negative risk factor. Carotid atherosclerosis is reduced in asthmatic patients treated with ICS compared with matched controls. This study suggests that ICS may have protective effects against atherosclerosis. Copyright©ERS 2010.


Matsunaga K.,Wakayama Medical University | Akamatsu K.,Wakayama Medical University | Miyatake A.,Miyatake Asthma Clinic | Ichinose M.,Tohoku University
Respiratory Medicine | Year: 2013

Background: The clinical features, physiology, and pathology of severe asthma are poorly understood. Recently, the forced vital capacity (FVC) has been shown to be reduced in severe asthma compared to mild asthma, possibly due to air trapping. However, the natural history and risk factors of obstructive change for such asthmatic patients have not been fully elucidated. Methods: We examined the data of a retrospective analysis of lung function changes over a 10-year period in 54 severe asthma patients. Results: The faster obstructive changes detected by FEV1 (forced expiratory volume in one second) were accompanied by excessive loss of FVC (r = 0.85, p < 0.0001) and the reduction in FVC was 1.2 times larger than the FEV1 change. Age, baseline FVC, exacerbation rate and oral corticosteroids use showed significantly negative correlations with the rate of annual change in FVC. Conclusions: These data indicate that the decline in FVC is more evident than FEV1 in severe asthma, suggesting that small airway susceptibility may be the cause of rapid disease progression. Aging, exacerbations of asthma, and use of systemic corticosteroids are related to excess FVC decline, particularly if FVC is still normal. © 2012 Published by Elsevier Ltd.


Yamaide F.,Chiba University | Undarmaa S.,Chiba University | Mashimo Y.,Chiba University | Shimojo N.,Chiba University | And 19 more authors.
International Archives of Allergy and Immunology | Year: 2013

Background: Matrix metalloproteinase 12 gene (MMP12) has been shown to be associated with asthma in a Caucasian population. In this study, we investigate whether single-nucleotide polymorphisms (SNPs) of MMP12 are associated with a risk for asthma in a Japanese population. Methods: We tested for an association between SNPs in MMP12 and asthma, including its severity, in a Japanese population (630 pediatric and 417 adult patients with atopic asthma and 336 children and 632 adults as controls). The rs652438 A and G variants (N357S) were generated by site-directed mutagenesis and an assay with artificial peptide substrates was used to compare two types of MMP12 activity. The effect of MMP12 inhibition with MMP12-specific small interfering RNA (siRNA) on chemokine secretion from airway epithelial cells was also tested in vitro. Results: N357S showed a p value <0.05 for childhood and combined (adult plus childhood) asthma in the dominant model [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.00-2.56, p = 0.047; OR 1.40, 95% CI 1.04-1.89, p = 0.028, respectively]. This risk variant is associated with asthma severity in adult patients. In the functional assay, the minor-allele enzyme showed significantly lower activity than the major-allele enzyme. MMP12-specific siRNA suppressed IP-10 secretion from airway epithelial cells upon stimulation with IFN-β. Conclusions: Our results suggest that MMP12 confers susceptibility to asthma and is associated with asthma severity in a Japanese population. MMP12 may be associated with asthma through inappropriate attraction of leukocytes to the inflamed tissue. © 2012 S. Karger AG, Basel.


Harada M.,Institute of Physical and Chemical Research | Hirota T.,Institute of Physical and Chemical Research | Jodo A.I.,Institute of Physical and Chemical Research | Hitomi Y.,Institute of Physical and Chemical Research | And 28 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2011

Thymic stromal lymphopoietin (TSLP) triggers dendritic cell - mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP) - 1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter - reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patientswith childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively).We further examined the effects of corticosteroids and a long-acting β2-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.


Chang W.-C.,Kaohsiung Medical University | Lee C.-H.,Kaohsiung Medical University | Hirota T.,RIKEN | Wang L.-F.,National Taiwan University | And 19 more authors.
PLoS ONE | Year: 2012

Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD. © 2012 Chang et al.


Hirota T.,RIKEN | Takahashi A.,RIKEN | Kubo M.,RIKEN | Tsunoda T.,RIKEN | And 24 more authors.
Nature Genetics | Year: 2011

Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87×10 -12), a locus on chromosome 10p14 (P = 1.79 ×-10-15) and a gene-rich region on chromosome 12q13 (P = 2.33 ×10 -13). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07× 10 -23), which is close to rs2070600, a SNP previously reported for association with FEV 1/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility. © 2011 Nature America, Inc. All rights reserved.

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