Takashi Naito

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.

Asthma Phenotypes in Japanese Adults - Their Associations with the CCL5 and ADRB2 Genotypes

BACKGROUNDnCluster analyses were previously performed to identify asthma phenotypes underlying asthma syndrome. Although a large number of patients with asthma develop the disease later in life, these previous cluster analyses focused mainly patients with younger-onset asthma.nnnMETHODSnCluster analysis examined the existence of distinct phenotypes of late-onset asthma in Japanese patients with adult asthma. We then associated genotypes at the CCL5, TSLP, IL4, and ADRB2 genes with the clusters of asthma identified.nnnRESULTSnUsing the 8 variables of age, sex, age at onset of the disease, smoking status, total serum IgE, %FEV(1), FEV(1)/FVC, and specific IgE responsiveness to common inhaled allergens, two-step cluster analysis of 880 Japanese adult asthma patients identified 6 phenotypes: cluster A (n = 155): older age at onset, no airflow obstruction; cluster B (n = 170): childhood onset, normal-to-mild airflow obstruction; cluster C (n = 119): childhood onset, the longest disease duration, and moderate-to-severe airflow obstruction; cluster D (n = 108): older age at onset, severe airflow obstruction; cluster E (n = 130): middle-age at onset, no airflow obstruction; and cluster F (n = 198): older age at onset, mild-to-moderate airflow obstruction. The CCL5-28C>G genotype was significantly associated with clusters A, B and D (OR 1.65, p = 0.0021; 1.67, 0.018; and 1.74, 0.011, respectively). The ADRB2 Arg16Gly genotype was also associated with clusters B and D (OR 0.47, p = 0.0004; and 0.63, 0.034, respectively).nnnCONCLUSIONSnThe current cluster analysis identified meaningful adult asthma phenotypes linked to the functional CCL5 and ADRB2 genotypes. Genetic and phenotypic data have the potential to elucidate the phenotypic heterogeneity and pathophysiology of asthma.BACKGROUNDnCluster analyses were previously performed to identify asthma phenotypes underlying asthma syndrome. Although a large number of patients with asthma develop the disease later in life, these previous cluster analyses focused mainly patients with younger-onset asthma.nnnMETHODSnCluster analysis examined the existence of distinct phenotypes of late-onset asthma in Japanese patients with adult asthma. We then associated genotypes at the CCL5, TSLP, IL4, and ADRB2 genes with the clusters of asthma identified.nnnRESULTSnUsing the 8 variables of age, sex, age at onset of the disease, smoking status, total serum IgE, %FEV1, FEV1/FVC, and specific IgE responsiveness to common inhaled allergens, two-step cluster analysis of 880 Japanese adult asthma patients identified 6 phenotypes: cluster A (n = 155): older age at onset, no airflow obstruction; cluster B (n = 170): childhood onset, normal-to-mild airflow obstruction; cluster C (n = 119): childhood onset, the longest disease duration, and moderate-to-severe airflow obstruction; cluster D (n = 108): older age at onset, severe airflow obstruction; cluster E (n = 130): middle-age at onset, no airflow obstruction; and cluster F (n = 198): older age at onset, mild-to-moderate airflow obstruction. The CCL5-28C>G genotype was significantly associated with clusters A, B and D (OR 1.65, p = 0.0021; 1.67, 0.018; and 1.74, 0.011, respectively). The ADRB2 Arg16Gly genotype was also associated with clusters B and D (OR 0.47, p = 0.0004; and 0.63, 0.034, respectively).nnnCONCLUSIONSnThe current cluster analysis identified meaningful adult asthma phenotypes linked to the functional CCL5 and ADRB2 genotypes. Genetic and phenotypic data have the potential to elucidate the pheno- typic heterogeneity and pathophysiology of asthma.

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

BackgroundAn Nrf2-dependent response is a central protective mechanism against oxidative stress. We propose that particular genetic variants of the Nrf2 gene may be associated with a rapid forced expiratory volume in one second (FEV1) decline induced by cigarette smoking.MethodsWe conducted a retrospective cohort study of 915 Japanese from a general population. Values of annual decline in FEV1 were computed for each individual using a linear mixed-effect model. Multiple clinical characteristics were assessed to identify associations with annual FEV1 decline. Tag single-nucleotide polymorphisms (SNPs) in the Nrf2 gene (rs2001350, rs6726395, rs1962142, rs2364722) and one functional SNP (rs6721961) in the Nrf2 promoter region were genotyped to assess interactions between the Nrf2 polymorphisms and smoking status on annual FEV1 decline.ResultsAnnual FEV1 decline was associated with smoking behavior and inversely correlated with FEV1/FVC and FEV1 % predicted. The mean annual FEV1 declines 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 (pcorr = 0.016). We also found a significant interaction between rs6726395 genotype and smoking status on the FEV1 decline (p for interaction = 0.011). The haplotype rs2001350T/rs6726395A/rs1962142A/rs2364722A/rs6721961T was associated with lower annual decline in FEV1 (p = 0.004).ConclusionsThis study indicated that an Nrf2-dependent response to exogenous stimuli may affect annual FEV1 decline in the general population. It appears that the genetic influence of Nrf2 is modified by smoking status, suggesting the presence of a gene-environment interaction in accelerated decline in FEV1.

Genome-wide association study for levels of total serum IgE identifies HLA-C in a Japanese population.

Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (nu200a=u200a1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (Pu200a=u200a1.07×10−10). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.

Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population

It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering.

A distinct sensitization pattern associated with asthma and the thymic stromal lymphopoietin (TSLP) genotype.

BACKGROUNDnAtopy 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.nnnMETHODSnWe 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.nnnRESULTSnIn 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).nnnCONCLUSIONSnCluster 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.

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.

Heritability of pulmonary function estimated from genome-wide SNPs in healthy Japanese adults

BACKGROUNDnPulmonary 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.nnnMETHODSnWe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnThis 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.

Variants near the HLA complex group 22 gene (HCG22) confer increased susceptibility to late-onset asthma in Japanese populations

To the Editor: Asthma is not a single disease but rather a complex syndrome driven by various interactions among genetic and environmental factors. Recent genetic studies, including genome-wide association studies (GWASs), have successfully identified many genetic loci responsible for susceptibility to asthma. However, these loci explain only a small proportion of the heritability of asthma. This is due in part to the phenotypic heterogeneity of asthma. Several unbiased cluster analyses have classified its heterogeneous phenotypic groups; these cluster analyses, including ours, have shown that one of the strong predictors for the distinguishing features of the different phenotypic groups of asthma is age of asthma onset. In addition, we have reported that genes encoding CCL5/ RANTES, tissue factor, Clara cell secretory protein, or catalase were associatedwith adult/late-onset asthma in a Japanese population. In the current study, assuming that differentiating asthma on the basis of age of onset of the disease increases the power of genetic studies and enhances the understandingof its pathogenesis, we performed a GWAS focusing on late-onset asthma (age of onset, >_40 years) in 3 Japanese populations. We conducted a 2-stage genetic association study of 4933 Japanese adults (see Fig E1 in this article’s Online Repository at www.jacionline.org). The participants’ characteristics are shown in Table E1 in this article’s Online Repository at www.jacionline. org, and the methods are described in detail in the Methods section in this article’s Online Repository at www.jacionline. org. First, we performed a genome-widemeta-analysis of GWASs of the 2 discovery samples (see Fig E2 in this article’s Online Repository at www.jacionline.org). A total of 473,981 single nucleotide polymorphisms (SNPs) were meta-analyzed, and 14 SNPs with P values of less than 1.0 3 10 were selected (see Table

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

BACKGROUNDnRecent 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.nnnMETHODSnWe 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.nnnRESULTSnThe A allele was associated with asthma (ORxa0=xa01.56; Mantel-Haenszel pxa0=xa00.0040) 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.nnnCONCLUSIONSnOur 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.