BackgroundIL1RL1 (ST2) is involved in Th2 inflammation including eosinophil activation. Single nucleotide polymorphisms (SNPs) of the IL1RL1 gene are associated with asthma development and increased peripheral blood eosinophil counts. However, the association between IL1RL1 SNPs and eosinophilic phenotype among adults with asthma remains unexplored.MethodsIn a primary cohort of 110 adult Japanese patients with stable asthma, we examined the associations between IL1RL1 SNPs and clinical measurements including forced expiratory volume (FEV1), airway reversibility of FEV1, exhaled nitric oxide (FeNO), serum soluble-ST2 (sST2) levels, peripheral blood eosinophil differentials and serum total IgE level. The findings in the primary cohort were confirmed in a validation cohort of 126 adult Japanese patients with stable asthma.ResultsPatients with minor alleles in 3 SNPs (rs17026974, rs1420101, and rs1921622) had high FeNO, blood eosinophil differentials, and reversibility of FEV1, but low levels of serum sST2 and FEV1. Minor alleles of rs1041973 were associated with low serum sST2 levels alone. In the validation cohort, minor alleles of rs1420101 were associated with high FeNO and blood eosinophil differentials, whereas minor alleles of rs17026974 and rs1921622 were associated with high blood eosinophil differentials and FeNO, respectively. Multivariate analyses revealed that the minor allele of rs1420101 additively contributed to the FeNO, blood eosinophil differentials, and reversibility of FEV1.ConclusionsThe minor alleles of IL1RL1 SNPs were associated with high FeNO and peripheral blood eosinophilia among adult Japanese patients with stable asthma. IL1RL1 SNPs may characterize the eosinophilic phenotype with greater eosinophilic inflammation in the Japanese asthma cohort.

Although associations between endotoxin exposure or respiratory infection and asthma have been recognized, the genetic effects in these conditions are unclear. Toll-like receptors (TLRs) play an essential role in innate host defense and in the control of adaptive immune responses. IL-1R-associated kinase-M (IRAK-M) and single immunoglobulin IL-1R-related molecule (SIGIRR) negatively regulate TLR-signaling pathways. To investigate whether polymorphisms in these genes were associated with asthma or asthma-related phenotypes, we screened these genes for polymorphisms by direct sequencing of 24 asthmatics and identified 19 variants in IRAK-M and 12 variants in SIGIRR. We next conducted linkage disequilibrium mapping of the genes, and examined the association of polymorphisms and haplotypes using 391 child patients with asthma, 462 adult patients with asthma, and 639 controls. None of the alleles or haplotypes of IRAK-M and SIGIRR were associated with asthma susceptibility or asthma-related phenotype. Our results indicate that polymorphisms in IRAK-M and SIGIRR are not likely to be associated with the development of asthma in the Japanese population.

BackgroundPulmonary function is a heritable trait, and recent genome-wide association studies (GWASs) have identified a number of loci influencing the trait. Genome-wide Complex Trait Analysis (GCTA) is a novel method provided by a software package that estimates the total additive genetic influence caused by common single nucleotide polymorphisms (SNPs) on whole-genome arrays. We conducted a GWAS and assessed the heritability of pulmonary function in an adult Japanese population using this approach.MethodsWe initially conducted a GWAS on %forced vital capacity (FVC), %forced expiratory volume (FEV1) and FEV1/FVC in healthy Japanese adults (N=967). We then examined the heritability of these traits using GCTA with a total of 480,026 SNPs. We also estimated the genetic impact of the 24 genes identified as susceptibility genes to FEV1/FVC in six previous GWASs on the heritability of FEV1/FVC in the Japanese population.ResultsThe heritabilities for %FVC, %FEV1, and FEV1/FVC were 71.2%, 51.9% and 41.6%, respectively. These results corresponded to previous heritability estimates for pulmonary function obtained by GCTA or by twin studies. The 24 previously reported pulmonary function genes accounted for 4.3−12.0% of the entire estimated heritability of FEV1/FVC.ConclusionsThis study demonstrated that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs in healthy Japanese adults. The pulmonary function genes reported in previous GWASs of non-Japanese populations showed a definite impact of the genes on FEV1/FVC, thus indicating the presence of common pathways related to this trait beyond ethnicity.

Background:Chronic rhinosinusitis (CRS), which is clinically classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), shows considerable geographic differences and heterogeneity. Eosinophilic (E) CRS with nasal polyps (ECRSwNP) has a higher degree of disease severity and higher frequency of comorbid asthma. Epidemiologic studies in different ethnic populations have improved understanding of the pathophysiology of the disease. Here we report the clinical characteristics of Japanese patients with medically refractory CRS undergoing endoscopic sinus surgery (ESS).Methods:We recruited a total of 210 CRS patients and assessed them by nasal endoscopy, the Lund-Mackay score using computed tomography (CT), peripheral eosinophilia and smoking status. We also examined the comorbidity of asthma, effects of age and lung functions in the patients.Results:In this study, 13% of CRSwNP patients and 20% of CRSwNP patients with peripheral blood eosinophilia exhibited obstructive lung dysfunction (FEV1/FVC < 70%) despite the absence of an asthma diagnosis. Among elderly nonsmoker patients (≥ 60 years) who had never been diagnosed with asthma, 50% of CRSwNP patients with peripheral blood eosinophilia showed decreased FEV1/FVC < 70%.Conclusions:Our findings suggest that asthma is under-diagnosed in CRS patients who undergo ESS, especially the elderly. Although the association between CRS and asthma has been recognized, increased attention to the comorbidity of obstructive airway diseases such as asthma is still needed for management of medically refractory CRS.

Allergic diseases are complex diseases caused by a combination of genetic and environmental factors. To determine the genetic components of these diseases and to discover the genes and cellular pathways underlying them, a large number of genetic studies have been conducted. Progress in genetics enables us to conduct genome-wide association studies (GWASs), which is a comprehensive and unbiased approach to identify susceptibility loci for multifactorial diseases. Recent GWASs have convincingly detected a large number of loci associated with allergic diseases. Candidate genes in the susceptibility loci suggest roles for epithelial barrier functions, innate-adaptive immunity, IL-1 family signaling, regulatory T cells and the vitamin D pathway in the pathogenesis of allergic diseases. Interestingly, the IL1RL1, HLA, IL13 and C11orf30 regions are overlapping susceptibility loci among atopic dermatitis and asthma or allergic rhinitis. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWASs improve our understanding of the pathophysiology of human allergic diseases and contribute to the development of better treatment and preventive strategies.

Bronchial asthma is a common inflammatory disease caused by a combination of genetic and environmental factors. To discover the genes and cellular pathways underlying asthma, a large number of genetic studies have been conducted. Genome-wide association studies (GWAS), which comprehensively assess genes related to multifactorial diseases and drug reactivity, have enhanced understanding of human diseases. From 2007, GWAS of susceptibility to asthma in Caucasian, Mexican, and African-ancestry populations have been conducted and several susceptible loci were identified. Recently, much larger consortium-based GWAS analyses of collaborative samples with adequate statistical power were performed, and the implicated genes suggested a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Furthermore, GWAS identified candidate loci associated with natural variations in lung function, blood eosinophilia and eosinophilic esophagitis, which is inflammation of the esophagus with abnormal infiltration of eosinophils in an allergic reaction. Comparing GWAS in asthma and these clinical phenotypes might help to clarify the mechanisms underlying asthma. Pharmacogenomics analyses using GWAS regarding genetic factors related to the effectiveness of inhaled corticosteroid (ICS) therapy and inhaled beta2-adrenergic agonists are ongoing now. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWAS provide valuable insights into the pathophysiology of asthma and contribute to the development of better treatment and preventive strategies.