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This article examines the impact of the COVID-19 pandemic on care-seeking patterns for hay fever in Japan. The study used a retrospective claims database cohort to analyze changes in outpatient visits and prescriptions for hay fever during the pandemic. The findings indicate a significant decrease in care-seeking behaviors for hay fever during the COVID-19 pandemic, likely due to lifestyle changes and preventive measures implemented to minimize SARS-CoV-2 exposure. However, the study acknowledges limitations in the data and calls for further research on the effects of pollen dispersion and longer prescription durations. [Extracted from the article]

ABSTRACT Background and objective: Genetic background is thought to be one of the risk factors for development of COPD. Recently, it has been proposed that the innate immune system is involved in the pathophysiology of COPD. We hypothesized that polymorphisms in the nucleotide-binding and oligomerization domain (NOD)1 and NOD2 genes would be associated with the pathogenesis of COPD. In addition, the associations between these single nucleotide polymorphisms (SNPs) and phenotypes of COPD were analysed. Methods: Japanese COPD patients ( n = 228) and non-COPD smokers ( n = 101) were recruited from the outpatient clinic at Kyoto University Hospital, Kyoto, Japan. At entry into the study, a blood sample was taken and a pulmonary function test was performed. Genotyping was performed for 6 selected tag SNPs of NOD1 and 5 tag SNPs of NOD2. Further investigations were performed for SNP that were associated with COPD, including baseline gene expression, the relative proportions of splicing variants in whole blood, responses to ligand and enhancement of gene expression in peripheral blood neutrophils stimulated with pro-inflammatory cytokines. Results: The distribution of NOD2 rs1077861 genotypes differed between Japanese COPD patients and non-COPD smokers ( P = 0.036). This SNP was also associated with a lower FEV1 % predicted (57.2 ± 1.8 for TT vs 50.8 ± 2.3 for TA/AA, P = 0.03) and DLCO/VA (2.89 ± 0.1 in TT vs 2.53 ± 0.14 in TA/AA, P = 0.036) in COPD patients. NOD2 gene expression after stimulation with 10 ng/mL of tumour necrosis factor-α for 4 h, was increased to a greater extent in TA/AA genotype than in TT genotype peripheral blood neutrophils ( P = 0.015). Conclusions: The NOD2 rs1077861 SNP may influence the development and progression of COPD in Japanese subjects. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is recognized as a major health problem worldwide, and its prevalence depends on the age range of the subjects. The aims of this study were to determine the current prevalence of AR, effects of age on the prevalence of IgE sensitization to inhalant allergens, and serum total IgE levels in Japanese subjects. Methods: We conducted a survey of 1,540 subjects between 20 and 49 years of age in 2006 and 2007 and examined the prevalence of AR and sensitization to 7 common aeroallergens. We measured serum total IgE and specific IgE to 7 aeroallergens. AR was determined based on symptoms, predominantly in the nose and eyes, caused by aeroallergens as mentioned in a questionnaire and sensitization to any of the 7 aeroallergens as assessed by measurement of serum specific IgE. Results: The prevalence of AR was 44.2% (681 of the 1,540 subjects) and there was no difference among age decades. Of the 1,540 subjects, 1,073 (69.7%) were sensitized to at least 1 of the 7 aeroallergens. The most common allergen in AR was Japanese cedar pollen (89.6%, 610 of the 681 with AR) in all the age decades examined. The sensitization rate to mites was significantly higher in the younger subjects. Conclusion: Our data suggest that the prevalence of AR between 20 and 49 years of age has increased by nearly 10% during the last 10 years. Cedar pollen and mites were predominant allergen sources among the 7 aeroallergens in the Japanese population. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Asthma is a complex phenotype that is influenced by both genetic and environmental factors. Genome-wide linkage and association studies have been performed to identify susceptibility genes for asthma. These studies identified new genes and pathways implicated in this disease, many of which were previously unknown. Objective: To perform a large-scale genotyping study to identify asthma-susceptibility genes in the Japanese population. Methods: We performed a large-scale, three-stage association study on 288 atopic asthmatics and 1032 controls, by using multiplex PCR-Invader assay methods at 82,935 single nucleotide polymorphisms (SNPs) (1st stage). SNPs that were strongly associated with asthma were further genotyped in samples from asthmatic families (216 families, 762 members, 2nd stage), 541 independent patients, and 744 controls (3rd stage). Results: SNPs located in the 5' region of PEX19 (rs2820421) were significantly associated with P < 0.05 through the 1st to the 3rd stage analyses; however, the P values did not reach statistically significant levels (combined, P = 3.8 x 10-5; statistically significant levels with Bonferroni correction, P = 6.57 x 10-7). SNPs on HPCAL1 (rs3771140) and on IL18R1 (rs3213733) were associated with asthma in the 1st and 2nd stage analyses, but the associations were not observed in the 3rd stage analysis. Conclusion: No association attained genome-wide significance, but several loci for possible association emerged. Future studies are required to validate these results for the prevention and treatment of asthma. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL)-13 has come to be appreciated as a molecule critically involved in allergic inflammatory responses. Recent studies revealed that a common variant in the coding region of the IL13 gene, Arg 110Gln, has been implicated in the development of asthma and atopy. Methods: To assess whether the IL13 variant Arg 110Gln is associated with cedar pollinosis, one of the most common atopic diseases in the Japanese population, we examined the Arg 110Gln variant using PCR-RFLP to compare the genotype and allele frequencies between 95 patients with cedar pollinosis and 95 healthy control subjects. Relationships between the Arg 110Gln variant and the pollinosis-related traits, e.g. rhinitis severity, eosinophil counts in nasal secretion and serum total and allergen-specific IgE levels, were also investigated. Results: The frequencies of the minor allele Gln110 were 25.8% in patients with cedar pollinosis and 30.9% in healthy control subjects (p > 0.05). There was also no significant difference in the genotype frequencies between cases and controls (p > 0.05). In addition, we found no significant association of the Arg110Gln variant with any of the pollinosis-related phenotypes (p > 0.05). Conclusions: Our data suggest lack of evidence for identifying the variant Arg110Gln at the IL13 locus as a genetic risk factor involved in the development of Japanese cedar pollinosis. [ABSTRACT FROM AUTHOR]

Sarcoidosis is known to be a systemic granulomatous disorder characterized by a cell-mediated Th1-type inflammatory response. To identify a key genetic factor in the pathogenesis of sarcoidosis, we investigated single nucleotide polymorphisms within 10 candidate genes involved in type 1 immune process (IFNA17, IFNB, IFNG, IFNGR1, IFNGR2, IL12B, IL12RB1, IL12RB2, ETA-1, and NRAMP1) in an association-based study of 102 Japanese patients with sarcoidosis, 114 with tuberculosis, and 110 control subjects. After correction for multiple testing, an IFNA17 polymorphism (551T→G) was found to be associated with susceptibility to sarcoidosis (odds ratio 3.27 [95% CI: 1.44–7.46], P=0.004, Pc=0.04), but not to tuberculosis. We observed no significant associations with the other polymorphisms of the Th1-related genes. We further typed another IFNA polymorphism (IFNA10 60T→A) and confirmed two major haplotypes of the IFNA gene, viz., allele 1: IFNA10 [60T]-IFNA17 [551T] and allele 2: IFNA10 [60A]-IFNA17 [551G], in the Japanese population. In healthy subjects, IFNA allele 2, which is over-represented in patients with sarcoidosis, was significantly associated with increased IFN-α and IL-12p70 production induced by Sendai virus in vitro. This study suggests that possession of the IFNA allele with higher levels of IFN-α significantly increases the risk of sarcoidosis. [ABSTRACT FROM AUTHOR]

There is heterogeneity in the pathophysiology of chronic rhinosinusitis (CRS). Obtaining a detailed understanding of patient profiles in specific regions can provide valuable information not only for clinical practice but also future research plans. The aim of this study was to investigate the characteristics of patients who underwent endoscopic sinus surgery (ESS) for CRS. This retrospective, single-center study examined the features of 453 patients with CRS who underwent ESS in the Tokyo area of Japan. The study evaluated various factors in patients with CRS including sex and age, the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score, the recurrence rate of CRS, comorbidities of asthma and/or allergic diseases, and IgE sensitization to 12 inhaled allergens. Age-related declines in the sensitization rate to inhaled allergens were observed, and the most notable age-related decrease in specific IgE antibodies was observed for house dust mites (HDM) (p = 8.3 × 10−7). Sensitization to HDM, cat dander, and various types of fungi, including Aspergillus , was frequently observed in the CRS with asthma group, with rates of 54%, 17%, and 17%, respectively. We found that 23% of the patients had recurrence. In the recurrence group, the positive rates of specific IgE antibodies for birch and cat dander were significantly higher than in the no recurrence group. Bronchial asthma was identified as an important factor for recurrence. Among male patients, the recurrence group was younger than the no-recurrence group (p = 0.0032). Severe eosinophilic CRS (ECRS) showed early recurrence after surgery, with over the half of the patients experiencing at least one recurrence within 2 years post-surgery. Among patients with ECRS, the recurrence rate for females was 1.92 times higher than for males. Our study revealed the influences of age and sex on various clinical phenotypes of CRS patients undergoing ESS. There was a high sensitization rate to cat dander in both the recurrence and asthma groups. Further research on diverse disease etiologies is necessary to improve therapeutic strategies for patients with CRS. [ABSTRACT FROM AUTHOR]

Adrenaline is the first-line medication for managing anaphylaxis. A better understanding of prescription trends for adrenaline auto-injectors (AAIs) is important to improving patient care as well as information on health education interventions and medical guidelines. However, it has been difficult to gather comprehensive data in a sustainable manner. Thus, we aimed to investigate trends in AAI prescriptions in Japan. We searched the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), a unique and comprehensive database of health insurance claims, and investigated prescriptions for AAIs for all ages (April 2017 to March 2018). We assessed the annual number of prescriptions per person as well as prescription rates per 100,000 population per year by age, sex, and geographic region. A total of 88,039 subjects (56,109 males, 31,930 female) and 116,758 devices (1.33 AAIs per patient per year) were prescribed AAIs at least once a year for all ages. The prescription rate for AAIs was 69.5 per 100,000 population-years. Patients aged 0–9 years were prescribed AAIs at the rate of 278.9 per 100,000 population-years. Patients aged 0–19 years were 6.4 times more likely to be prescribed AAIs than those over 20 years of age. Males were more frequently prescribed AAIs than females in all age groups, except for those aged 20–24 years. We also evaluated differences in prescription rates by geographic region. This comprehensive evaluation revealed trends in AAI prescriptions, thus helping develop preventive strategies with respect to anaphylaxis in Japan. [ABSTRACT FROM AUTHOR]

Background: Receptor-interacting protein (RIP)-2 is a serine/threonine kinase containing a caspase recruitment domain (CARD) that is involved in the Toll-like receptor-signaling pathway. Although associations between endotoxin exposure or respiratory infection and asthma have been recognized, the genetic influences in these conditions are unclear. The aim of our study was to examine whether polymorphisms or haplotypes in RIP2 were associated with childhood atopic asthma in a Japanese population. Methods: We screened the RIP2 gene for polymorphisms by direct sequencing and characterized the linkage disequilibrium (LD) mapping of the gene. Seven variants were genotyped in childhood atopic asthma (n = 300) and normal controls (n = 637). We conducted case-control and case-only association studies between the variants and asthma-related phenotypes. Haplotype association analyses were also performed. Results: A total of 31 variants were identified and none of the alleles or haplotypes of RIP2 were associated with asthma susceptibility. In the case-only study, an association between an RIP2 promoter polymorphism and childhood severe asthma (P=0.0032;odds ratio (OR) 3.37, 95% confidence interval (CI) 1.45-7.87) was observed. Conclusions: Although polymorphisms in RIP2 are not likely to be associated with the development of asthma, the genetic variants might contribute to asthma severity in the Japanese population. [ABSTRACT FROM AUTHOR]

Signal transducers and activators of transcription 6 (Stat6) is involved in the interleukin (IL)-4 and IL-13 signaling pathway. The aim of the present study was to evaluate whether polymorphisms in the 5′-flanking region of the Stat6 gene are associated with allergic diseases in Japanese children. The Stat6 gene polymorphisms were genotyped by polymerase chain reaction (PCR) fragment length polymorphism analysis and the IL-4 receptor Ile50Val polymorphism was examined using PCR methods. Novel dinucleotide repeat polymorphisms were found in the 5′-flanking sequences, positioning at −865 (Pro A) and −690 (Pro B) of the Stat6 gene starting codon. The GT repeats in the 5′-flanking sequences were highly polymorphic (Pro A: 14−29 repeats; ProB: 14−20 repeats) with no significant differences in the frequency of allelic and genotypic distributions observed between allergic subjects and controls. In the GT repeat polymorphism of Stat6 exon 1, there was a significant difference in the frequency of genotypic distribution between the two groups ( P = 0.003). The Stat6 exon 1 variant had significant linkage disequilibrium with Pro B variants, but not with Pro A. The GT repeat polymorphism was not associated with the IL-4 receptor Ile50Val polymorphism. Variants of the Stat6 gene may be useful markers for predicting allergic diseases in Japanese children. [ABSTRACT FROM AUTHOR]

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Biologics are increasingly being used in patients with severe uncontrolled asthma. However, the trends in their use for treating severe asthma in Japan remain unclear., Methods: The number of patients with asthma prescribed omalizumab or mepolizumab between April 2017 and March 2018 was estimated according to sex, age, and geographical region using data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan., Results: Overall, 5,014, 3,449 and 7,977 patients were prescribed omalizumab, mepolizumab, or either combination, respectively. The total number of patients prescribed biologics displayed a bimodal distribution with peaks in their early teens and seventies. Biologics were most commonly used by male and female patients in their seventies. Prescription was 1.24 times higher in males than in females up to the teenage years, whereas it was 1.95 times higher in females than in males from their twenties onwards. Omalizumab was prescribed 1.45 times more frequently than mepolizumab, especially in pediatric patients, and was prescribed 1.96 times more often to female patients than to male patients. Regional differences were observed in the proportion of patients prescribed biologics. Correlation analysis suggested a weak relationship (r = 0.3226, p = 0.0270) between the proportion of patients prescribed biologics and board-certified allergists according to the geographic region., Conclusions: In Japan, biologics are prescribed more often to older patients with severe asthma compared to those in other countries. Thus, eliminating the regional disparities in asthma treatment by specialists is necessary to provide appropriate medical care to patients with severe asthma., Competing Interests: Declaration of competing interest YN received consulting fees and an honorarium for speakers bureaus from Novo Nordisk, Daiichi Sankyo, and Sanofi. TM received consulting fees from the Health Insurance Claims Review & Reimbursement services. HM received a research grant from GlaxoSmithKline Japan that was unrelated to the submitted work. TIno received a research grant from Johnson & Johnson Vision Care, SEED Co., Ltd., Novartis Pharma K·K., and Kowa Company, Ltd that was unrelated to the submitted work, consulting fees from Santen Pharmaceutical Co., Ltd. and InnoJin, Inc., and stock or stock options from InnoJin, Inc. MF received an honorarium for speakers bureaus from Sanofi K·K., Kyorin Pharmaceutical Co., Ltd., and Novartis Pharma Co., Ltd. The other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: In 2022, the "New Capitalism Grand Design and Implementation Plan" was adopted in Japan, emphasizing the promotion and environmental development of startups. Given this context, an investigation into the startup and investment landscape in the allergy sector, both domestically and internationally, becomes imperative., Methods: We analyzed 156 allergy-related startups from Japan, the US, and Europe from 2010 to 2021. Data on corporate information and investment trends were extracted from databases and VC websites., Results: The total investment reached approximately 7.2 billion USD, with a ratio of 20:6:1 for the US, Europe, and Japan, respectively. The US showed a decline post its peak from 2016-2018, while Europe and Japan experienced growth. Notably, the US primarily invested in biopharmaceuticals for atopic dermatitis and food allergies, Europe in asthma-related apps, and Japan in healthcare apps and cross-border startups., Discussion and Conclusion: While Japan's investment environment in the allergy sector remains in its nascent stages and has room for development, the US and Europe are evidently ahead. Considering the rise of startups and funding limitations in Japan, external funding from regions like the US becomes a potential avenue. These findings are anticipated to contribute to the strategic activation of startups in allergy research and development.

ETS variant transcription factor 4 (ETV4) is a recently identified transcription factor that regulates gene expression-based biomarkers of asthma and IL6 production in an airway epithelial cell line. Given that ETV4 has not yet been implicated in asthma genetics, we performed genetic association studies of adult asthma in the ETV4 region using two independent Japanese cohorts (a total of 1532 controls and 783 cases). SNPs located between ETV4 and mesenchyme homeobox 1 (MEOX1) were significantly associated with adult asthma, including rs4792901 and rs2880540 (P = 5.63E-5 and 2.77E-5, respectively). The CC haplotype of these two SNPs was also significantly associated with adult asthma (P = 8.43E-7). Even when both SNPs were included in a logistic regression model, the association of either rs4792901 or rs2880540 remained significant (P = 0.013 or 0.007, respectively), suggesting that the two SNPs may have independent effects on the development of asthma. Both SNPs were expression quantitative trait loci, and the asthma risk alleles at both SNPs were correlated with increased levels of ETV4 mRNA expression. In addition, the asthma risk allele at rs4792901 was associated with increased serum IL6 levels (P = 0.041) in 651 healthy adults. Our findings imply that ETV4 is involved in the pathogenesis of asthma, possibly through the heightened production of IL6., (© 2021. The Author(s).)

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10 -12 ). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10 -12 ), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10 -7 ). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Background: Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases caused by complex gene-environment interactions. A functional single nucleotide polymorphism of cadherin-related family member 3 (CDHR3), known as a receptor of rhinovirus-C, is associated with childhood-onset asthma especially in atopic individuals., Objective: Here, we identified risk factors for adult-onset asthma and COPD, focusing on the impact of the CDHR3 variant in atopic individuals., Methods: We conducted a longitudinal, retrospective, observational cohort study of 1523 healthy adults with baseline examinations at Tsukuba Medical Center Hospital in 2008 and retrospectively identified new-onset, physician-diagnosed asthma or COPD from 2009 to 2018. We assessed risk factors by the Cox regression analysis. The impact of CDHR3 variant rs6967330 was also examined in individuals with pre-existing atopy., Results: Over 10 study years, 103 people developed airway diseases (79 asthma and 24 COPD; 52 females, average onset-age 55 years old, range 38-80). Higher body mass index (BMI) and lower forced expiratory volume in one second/forced vital capacity (FEV 1 /FVC) ratio were significant risk factors (BMI: HR 1.072 [95% CI 1.005-1.14], P = .034; FEV 1 /FVC ratio: HR 1.091 [1.044-1.14], P = .00011). Restriction to atopic individuals saw the A allele at rs6967330 and lower FEV 1 /FVC ratio to associate with adult-onset disease (A allele: HR 2.89 [1.57-5.20], P = .00062; FEV 1 /FVC ratio: HR 1.10 [1.04-1.17], P = .0010)., Conclusion and Clinical Relevance: Genetic susceptibility to rhinovirus-C infection in atopic individuals is a risk factor for chronic airway diseases even in later life., (© 2020 John Wiley & Sons Ltd.)

Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology (Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKA by the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030 is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10 -9 ). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

Background: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP)., Objectives: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy., Methods: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects., Results: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10 -24 for rs9271588 and P = 2.96 × 10 -24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10 -9 ). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10 -8 )., Conclusions: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes., Methods: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters., Results: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027)., Conclusions: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

Background: Recent 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., Methods: We 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., Results: The 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., Conclusions: Our 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., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

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.

Background: Filaggrin (FLG) is a major protein component of the stratum corneum (SC) layer, and FLG loss-of-function mutations are a predisposing factor for atopic dermatitis (AD). Previous cohort studies of children from northern and western Europe have reported FLG loss-of-function mutation frequencies of 15.1-20.9% and 5.8-13.0% in AD and non-AD groups, respectively., Objective: To elucidate the association between AD prevalence of FLG loss-of-function mutation carriers and climate conditions, we determined the AD prevalence and FLG loss-of-function mutation frequencies in a cohort of children from Ishigaki Island. Ishigaki Island has a subtropical climate with high humidity (monthly average, 60.8-78.7%) and high temperature (monthly average, 18.5-29.4°C) throughout the year., Methods: We diagnosed AD prevalence and analyzed eight FLG loss-of-function mutations in the Japanese population against a cohort of 721 children from the Kyushu University Ishigaki Atopic Dermatitis Study (KIDS) cohort. Parents gave consent for the mutation analysis during their medical examinations from 2001 to 2006., Results: Average AD prevalence was 7.3% per year, and a total of 127 children (17.6%) were diagnosed with AD at least once between 2001 and 2006. The average total serum IgE level differed significantly between the AD and non-AD groups (199.0 and 69.0IU/ml, respectively). Although five kinds of FLG loss-of-function mutations isolated in previous Japanese FLG mutation studies were identified, the FLG loss-of-function mutation frequency in children of the KIDS cohort was not significantly different between the AD and non-AD groups (7.9% and 6.1%, respectively; P=0.174)., Conclusion: The FLG loss-of-function mutation frequency was not significantly different between the AD and non-AD groups in a cohort of children from Ishigaki Island, which has a subtropical climate, suggesting that FLG loss-of-function mutations are not always a predisposing factor for AD prevalence., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.

Background: Atopy is a phenotypically heterogeneous condition, and the extent to which atopy accounts for asthma is controversial. In this study, we aimed to identify the presence of distinct sensitization patterns to common inhaled allergens and their association with asthma, allergic rhinitis and TSLP genotypes., Methods: We studied 1683 adults from Tsukuba, a city in central Japan and 297 adults from Kamishihoro, a cedar-free, birch-dominant town in northern Japan. Levels of total serum IgE and specific IgE antibodies towards 14 major inhaled allergens were measured. With the use of these measures, cluster analysis was applied to classify the subjects' sensitization patterns. We also examined the genetic effects of 2 TSLP functional SNPs on the development of each sensitization pattern., Results: In the Tsukuba study, cluster analysis identified four clusters, including "Dust mite dominant", "Multiple pollen", "Cedar dominant", and "Low reactivity". In the Kamishihoro study, "Dust mite dominant", "Multiple pollen" and "Low reactivity" clusters were also identified, but a "Cedar dominant" cluster was not formed. The association with asthma was strongest for the "Dust mite dominant" cluster in both the Tsukuba and the Kamishihoro studies. In never smokers, both SNPs were associated with the "Dust mite dominant" cluster (OR > 1.2). In contrast, in current or past smokers, these alleles were inversely associated with the "Multiple pollen" cluster (OR < 0.5)., Conclusions: Cluster analysis identified the presence of distinct sensitization patterns to common inhaled allergens. TSLP may cause asthma by promoting innate allergic responses to indoor allergens and this contribution is significantly modified by smoking.

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.

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.

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.

Tissue factor (TF) is important for initiation of coagulation and for the increased thrombin activity observed at sites of inflammation. Thrombin activity is induced by allergen challenge in asthmatic airways and is involved in the pathogenesis of asthma. A -603A --> G polymorphism (rs1361600) in the promoter region of the TF gene has been associated with serum TF levels and with the development of cardiovascular diseases. The aim of this study was to determine whether the functional -603A --> G polymorphism has genetic influences on the development of asthma. Case-control analysis was performed of the association between six common single-nucleotide polymorphisms (SNPs), including the -603A --> G polymorphism, at the TF gene, and the development of asthma, using two unrelated Japanese populations. In the primary population (n=826), the GG genotype at the -603A --> G polymorphism was associated with adult-onset asthma (onset at >or=21 years of age) (odds ratio (OR) 2.886, P=0.0231). A second population showed a similar tendency (n=1654, OR 1.602, P=0.064). Transcriptional activity of promoters with -603A --> G genotypes were examined using luciferase promoter assays. The -603G allele was associated with higher promoter activity (P<0.05). The association between the functional polymorphism (-603A --> G) in the TF gene promoter and adult-onset asthma indicates that TF is a candidate gene contributing to asthma susceptibility.

Background: Bronchial asthma is a chronic airway disorder characterized by bronchial inflammation. Oxidative stress is a key component of inflammation. Glutathione S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays a key role in cellular protection against oxidative stress. Several studies have shown that the GSTP1 geneis involved in the pathogenesis of asthma and a gene-gene interaction may occur within the GST gene superfamily., Methods: We screened single-nucleotide polymorphisms (SNPs) at the GSTP1 locus and performed an association study in the Japanese population using two independent case-control groups (group 1: 391 pediatric patients with asthma, 462 adult patients with asthma, and 639 controls, and group 2: 115 pediatric patients with asthma and 184 controls). The effect of GSTM1 null/present genotype on the association between GSTP1 Ile105Val and asthma was also investigated., Results: We identified 20 SNPs at this locus and found this region consisted of one linkage disequilibrium block represented by four SNPs (tag SNPs). The association between the Ile105Val polymorphism in the GSTP1 gene and childhood asthma was significant in both groups (p = 0.047 in group 1, and p = 0.021 in group 2). This association was only significant in patients with GSTM1-positive genotype in both groups (group 1: GSTM1 present p = 0.013 and GSTM1 null p = 0.925, and group 2: GSTM1 present p = 0.015 and GSTM1 null p = 0.362)., Conclusions: These findings suggest that the GSTP1 gene is a childhood asthma susceptible gene, and the GSTM1 gene is a modifier gene of GSTP1 for the risk of childhood asthma in the Japanese population., (Copyright 2007 S. Karger AG, Basel.)

Tumor necrosis factor (TNF) is a potent inflammatory cytokine that contributes to airway inflammation in asthma. Previous studies have reported that a G-to-A transition at position -308 (-308G/A, also referred to as TNF-alpha-308*1 and 308*2 respectively), is associated with asthma, but other studies have shown conflicting results. To investigate a possible association between the TNF-308G/A polymorphism and asthma, we performed transmission disequilibrium tests and a case-control study (family samples: 495 members in 165 Japanese trio families with one asthmatic child and both parents; case-control samples: 461 Japanese asthmatic children and 465 healthy controls). To increase the sample size and power, we performed a meta-analysis of all available relevant studies, including 2,477 asthmatics and 3,217 controls. We did not find a significant association between the TNF-308G/A polymorphism and childhood atopic asthma in two independent Japanese populations (P>0.05); however, meta-analysis revealed that the TNF-308G/A polymorphism was statistically significantly associated with asthma. The combined odds ratio with a fixed effects model and with a random effects for TNF-308A was 1.46 (95% confidence interval [CI], 1.27-1.68, P=0.0000001) and 1.46 (95% CI, 1.20-1.77, P=0.00014) respectively. Our data further support the importance of the TNF region in the development of asthma.

Atopic dermatitis (AD) is frequently associated with eosinophilia, highly elevated immunoglobulin E (IgE) levels and increased levels of T-helper 2-type (Th2) cytokines in skin lesions due to infiltrating T cells. Interleukin-12 (IL-12), in combination with interferon-gamma (IFN-gamma), inhibits IgE synthesis and Th2 cell function. As the IFN-gamma-inducing cytokines IL-12 and IL-23 utilize IL-12Rbeta1 as part of their receptors, it is possible that polymorphic variants of the IL-12Rbeta1 (IL12RB1) gene might determine an individual's susceptibility to AD. Here, we carried out a systemic search for genetic variants of the human IL12RB1 in Japanese subjects and identified 48 genetic variants. In a case-control association study, we found that promoter polymorphisms -111A/T and -2C/T were significantly associated with an increased risk of AD under a recessive model. The -111T-allele frequency in the independent population of child asthmatics was also much higher than that in the control group. In addition, the -111T/T genotype was progressively more common in AD with high total serum IgE levels in an IgE-level-dependent manner. Deletion analysis of the IL12RB1 promoter suggested that the -265 to -104 region that contained the -111A/T polymorphic site harbored an important regulatory element. Furthermore, we showed that the -111A/T substitution appeared to cause decreased gene transcriptional activity such that cells from -111A/A individuals exhibited higher IL12RB1 mRNA levels than those from -111T allele carriers. Our results suggested that in individuals with the -111T/T genotype, reduced IL-12Rbeta1 expression may lead to increased Th2 cytokine production in the skin and contribute to the development of AD and other subsequent allergic diseases.

The extracellular matrix glycoprotein tenascin-C (TNC) has been accepted as a valuable histopathological subepithelial marker for evaluating the severity of asthmatic disease and the therapeutic response to drugs. We found an association between an adult asthma and an SNP encoding TNC fibronectin type III-D (Fn-III-D) domain in a case-control study between a Japanese population including 446 adult asthmatic patients and 658 normal healthy controls. The SNP (44513A/T in exon 17) strongly associates with adult bronchial asthma (chi2 test, P=0.00019, Odds ratio=1.76, 95% confidence interval=1.31-2.36). This coding SNP induces an amino acid substitution (Leu1677Ile) within the Fn-III-D domain of the alternative splicing region. Computer-assisted protein structure modeling suggests that the substituted amino acid locates at the outer edge of the beta-sheet in Fn-III-D domain and causes instability of this beta-sheet. As the TNC fibronectin-III domain has molecular elasticity, the structural change may affect the integrity and stiffness of asthmatic airways. In addition, TNC expression in lung fibroblasts increases with Th2 immune cytokine stimulation. Thus, Leu1677Ile may be valuable marker for evaluating the risk for developing asthma and plays a role in its pathogenesis.

Background: IL-12 is a heterodimeric proinflammatory cytokine that forms a link between innate and adaptive immunity. Although associations between polymorphisms of IL-12B on chromosome 5q31-33 and asthma have been reported, the genetic influences of the polymorphisms and haplotype of IL-12B are unclear., Objective: To examine whether polymorphisms in IL-12B are associated with childhood atopic asthma in a Japanese population., Methods: We identified a total of 13 polymorphisms and characterized the linkage disequilibrium mapping of the gene. Three variants in the promoter and 3' untranslated region were genotyped, and we conducted case-control and case-only association studies between those variants and asthma-related phenotypes (childhood atopic asthma, n = 297; normal controls, n = 555). Haplotype association analysis and functional analysis of these variants were also performed., Results: 3' Untranslated region 10841C > A was significantly associated with the risk of childhood atopic asthma (P = .00062). The -6415 promoter variant, in linkage disequilibrium with the 10841C > A (D' = 0.78 and r2 = 0.61), was also marginally associated with childhood atopic asthma (P = .051). We analyzed the 2-locus haplotype by using these 2 polymorphisms and found a positive association with haplotype CTCTAA-C (-6415 CTCTAA and 10841C; P = .00078). Furthermore, 10841C > A affects the stability of transcripts, and promoter variant -6415GC enhances the transcriptional level of IL-12B., Conclusion: Our results imply that functional haplotype CTCTAA-C, which affects the instability of transcripts and the lower transcriptional level of IL-12B, has a protective effect in childhood atopic asthma. On the basis of these findings, the IL-12B gene might be involved in the development of atopic asthma through functional genetic polymorphisms.

Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control interferon-gamma (IFN-gamma) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter -1993T-->C SNP, which is in linkage disequilibrium with a synonymous coding 390A-->G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA; P = 0.004, P(c) = 0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P = 0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the -1993T-->C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the -1993 position, resulting in increased transcriptional activity of the TBX21 gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-gamma) production in human airways of individuals with the -1993T-->C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.

Bronchial asthma (BA) is a common chronic inflammatory disease characterized by hyperresponsive airways, excess mucus production, eosinophil activation, and the production of IgE. The complement system plays an immunoregulatory role at the interface of innate and acquired immunities. Recent studies have provided evidence that C3, C3a receptor, and C5 are linked to airway hyperresponsiveness. To determine whether genetic variations in the genes of the complement system affect susceptibility to BA, we screened single nucleotide polymorphisms (SNPs) in C3, C5, the C3a receptor gene (C3AR1), and the C5a receptor gene (C5R1) and performed association studies in the Japanese population. The results of this SNP case-control study suggested an association between 4896C/T in the C3 gene and atopic childhood BA (P = 0.0078) as well as adult BA (P = 0.010). When patient data were stratified according to elevated total IgE levels, 4896C/T was more closely associated with adult BA (P = 0.0016). A patient-only association study suggested that severity of childhood BA was associated with 1526G/A of the C3AR1 gene (P = 0.0057). We identified a high-risk haplotype of the C3 gene for childhood (P = 0.0021) and adult BA (P = 0.0058) and a low-risk haplotype for adult BA (P = 0.00011). We also identified a haplotype of the C5 gene that was protective against childhood BA (P = 1.4 x 10(-6)) and adult BA (P = 0.00063). These results suggest that the C3 and C5 pathways of the complement system play important roles in the pathogenesis of BA and that polymorphisms of these genes affect susceptibility to BA.

Several studies have shown linkage of chromosome region 12q13-24 to bronchial asthma and related phenotypes in ethnically diverse populations. In the Japanese population, a genome-wide study failed to show strong evidence of linkage of this region. Chromosome 12 genes that showed association with the disease in at least one report include: the signal transducer and activator of transcription 6 gene ( STAT6), the nitrogen oxide synthetase 1 gene ( NOS1), the interferon gamma gene ( IFNG), and the activation-induced cytidine deaminase gene ( AICDA). To evaluate the linkage between chromosome 12 and childhood asthma in the Japanese population, we performed sib-pair linkage analysis on childhood asthma families using 18 microsatellite markers on chromosome 12. To investigate association between chromosome 12 candidate genes and asthma, distributions of alleles and genotypes of repeat polymorphisms of STAT6, NOS1, and IFNG were compared between controls and patients. Single nucleotide polymorphism of AICDA was also investigated. Chromosome region 12q24.23-q24.33 showed suggestive linkage to asthma. The NOS1 intron 2 GT repeat and STAT6 exon 1 GT repeat were associated with asthma. Neither the IFNG intron 1 CA repeat nor 465C/T of AICDA showed any association with asthma. Our results suggest that NOS1 and STAT6 are asthma-susceptibility genes and that chromosome region 12q24.23-q24.33 contains other susceptibility gene(s).