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Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator

ABSTRACT: Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults. Yamada, Motoike, Kojima et al. undertake a GWAS study on 19,722 participants from two Japanese populations for lung function with adjustment for fractional exhaled nitric oxide levels to account for airway inflammation. The authors identify variants of the RNF5/AGER locus and explore their three-dimensional protein interactions to better investigate the association between these variants and lung function.

SUBMITTER: Yamada M

PROVIDER: S-EPMC8593164 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Genetic variations in nitric oxide synthase and arginase influence exhaled nitric oxide levels in children.

Project description:BackgroundExhaled nitric oxide (FeNO) is a biomarker of airway inflammation. In the nitric oxide (NO) synthesis pathway, nitric oxide synthases (encoded by NOS1, NOS2A, and NOS3) and arginases (encoded by ARG1 and ARG2) compete for L-arginine. Although FeNO levels are higher in children with asthma/allergy, influence of these conditions on the relationships between variations in these genes and FeNO remains unknown. The aims of the study were to evaluate the role of genetic variations in nitric oxide synthases and arginases on FeNO in children and to assess the influence of asthma and respiratory allergy on these genetic associations.MethodsAmong children (6-11 years) who participated in the southern California Children's Health Study, variations in these five genetic loci were characterized by tagSNPs. FeNO was measured in two consecutive years (N = 2298 and 2515 in Years 1 and 2, respectively). Repeated measures analysis of variance was used to evaluate the associations between these genetic variants and FeNO.ResultsSequence variations in the NOS2A and ARG2 loci were globally associated with FeNO (P = 0.0002 and 0.01, respectively). The ARG2 association was tagged by intronic variant rs3742879 with stronger association with FeNO in asthmatic children (P-interaction = 0.01). The association of a NOS2A promoter haplotype with FeNO varied significantly by rs3742879 genotypes and by asthma.ConclusionVariants in the NO synthesis pathway genes jointly contribute to differences in FeNO concentrations. Some of these genetic influences were stronger in children with asthma. Further studies are required to confirm our findings.

| S-EPMC3058253 | biostudies-literature

Exhaled Nitric Oxide Levels Among Adults With Excessive Alcohol Consumption.

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| S-EPMC4980555 | biostudies-literature

Elevated exhaled nitric oxide in allergen-provoked asthma is associated with airway epithelial iNOS.

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| S-EPMC3938593 | biostudies-literature

Nitric oxide enhances Th9 cell differentiation and airway inflammation.

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| S-EPMC4131005 | biostudies-literature

Genetic and epigenetic variations in inducible nitric oxide synthase promoter, particulate pollution, and exhaled nitric oxide levels in children.

Project description:BackgroundInducible nitric oxide synthase (iNOS; encoded by nitric oxide synthase isoform 2 [NOS2]) is the major enzyme for nitric oxide synthesis in airways. As such, measurement of fractional concentration of exhaled nitric oxide (Feno) provides an in vivo assessment of iNOS activity. Short-term exposure to air pollution, haplotypes, and DNA methylation in the NOS2 promoter has been associated independently with iNOS expression, Feno levels, or both.ObjectiveWe aimed to examine the effects of ambient air pollutants, NOS2 promoter haplotypes, and NOS2 promoter methylation on Feno levels in children.MethodsWe selected 940 participants in the Children's Health Study who provided buccal samples and had undergone Feno measurement on the same day. DNA methylation was measured with a bisulfite-PCR Pyrosequencing assay. Seven single nucleotide polymorphisms captured the haplotype diversity in the NOS2 promoter. Average particulate matter with an aerodynamic diameter of 2.5 ?m or less (PM(2.5)) and 10 ?m (PM(10)) or less and ozone and nitrogen dioxide levels 7 days before Feno measurement were estimated based on air pollution data obtained at central monitoring sites.ResultsWe found interrelated effects of PM(2.5), NOS2 promoter haplotypes, and iNOS methylation on Feno levels. Increased 7-day average PM(2.5) exposure was associated with lower iNOS methylation (P = .01). NOS2 promoter haplotypes were globally associated with NOS2 promoter methylation (P = 6.2 × 10(-8)). There was interaction among 1 common promoter haplotype, iNOS methylation level, and PM(2.5) exposure on Feno levels (P(interaction) = .00007).ConclusionPromoter variants in NOS2 and short-term PM(2.5) exposure affect iNOS methylation. This is one of the first studies showing contributions of genetic and epigenetic variations in air pollution-mediated phenotype expression.

| S-EPMC3487398 | biostudies-literature

Treatment of chronic obstructive pulmonary disease in patients with different fractional exhaled nitric oxide levels.

Project description:Some patients with chronic obstructive pulmonary disease (COPD) have eosinophilic inflammation which may be evaluated via the measurement of fractional exhaled nitric oxide (FeNO) like asthma. The aim of this prospective study was to assess whether FeNO levels can be used to identify patients with COPD with eosinophilic inflammation who may respond to inhaled corticosteroid (ICS) therapy.This study included patients (N?=?112) with COPD (age >18 years) who were divided into 4 groups depending upon whether they had high (?25 parts per billion [ppb]) or low (<25 ppb) pretreatment (baseline) FeNO and if they were treated with either ICS plus long-acting ?-agonist (ICS?+?LABA) or a long-acting muscarinic antagonist (LAMA). The 4 groups were: high FeNO/ICS?+?LABA, high FeNO/LAMA, low FeNO/ICS?+?LABA, and low FeNO/LAMA. Outcomes assessed included FeNO, COPD assessment test (CAT), and pulmonary function.The high FeNO/ICS?+?LABA group had the greatest reduction from baseline in FeNO levels (-25.80 ppb?±?27.14) compared with the high FeNO/LAMA, low FeNO/ICS?+?LABA, and low FeNO/LAMA groups (range, -4.45 to 1.31 ppb; P?<?.001). The high FeNO/ICS?+?LABA group also showed the greatest improvement in CAT (-7.20), which was statistically larger than the low FeNO/ICS?+?LABA and low FeNO/LAMA groups (-1.72 and -2.03, respectively). No difference in pulmonary function following treatment was observed across the 4 groups.This study found that patients with high FeNO showed the greatest reduction in FeNO and improvement in CAT with ICS?+?LABA therapy, supporting the use of FeNO to identify patients who would benefit from ICS use.

| S-EPMC6392665 | biostudies-literature

History of tuberculosis is associated with lower exhaled nitric oxide levels in HIV-infected children.

Project description:ObjectiveHIV disrupts host defense mechanisms and maintains chronic inflammation in the lung. Nitric oxide is a marker of lung inflammation and can be measured in the exhaled air. We investigated the relationship between exhaled nitric oxide (eNO), HIV status and airway abnormalities in perinatally HIV-infected children aged 6-19 years.DesignA cross-sectional study.MethodsHIV-infected individuals on antiretroviral therapy and HIV-uninfected children with no active tuberculosis (TB) or acute respiratory tract infection were recruited from a public hospital in Harare, Zimbabwe. Clinical history was collected and eNO testing and spirometry was performed. The association between eNO and explanatory variables (HIV, FEV1 z-score, CD4 cell count, viral load, history of TB) was investigated using linear regression analysis adjusted for age, sex and time of eNO testing.ResultsIn total, 222 HIV-infected and 97 HIV-uninfected participants were included. Among HIV-infected participants, 57 (25.7%) had a history of past TB; 56 (25.2%) had airway obstruction, but no prior TB. HIV status was associated with lower eNO level [mean ratio 0.79 (95% confidence interval, 95% CI 0.65-0.97), P = 0.03]. Within the HIV-infected group, history of past TB was associated with lower eNO levels after controlling for age, sex and time of eNO testing [0.79 (95% CI 0.67-0.94), P = 0.007].ConclusionHIV infection and history of TB were associated with lower eNO levels. eNO levels may be a marker of HIV and TB-induced alteration in pulmonary physiology; further studies focused on potential causes for lower eNO levels in HIV and TB are warranted.

| S-EPMC6687035 | biostudies-literature

Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide levels in bronchiectatic patients with and without primary ciliary dyskinesia.

Project description:BackgroundPrimary ciliary dyskinesia (PCD) is associated with chronic airway inflammation resulting in bronchiectasis.MethodsThe levels of exhaled nitric oxide (eNO), carbon monoxide (eCO) and nasal NO (nNO) from bronchiectatic patients with PCD (n=14) were compared with those from patients with non-PCD bronchiectasis without (n=31) and with cystic fibrosis (CF) (n=20) and from normal subjects (n=37) to assess the clinical usefulness of these measurements in discriminating between PCD and other causes of bronchiectasis.ResultsExhaled NO levels were lower in patients with PCD than in patients with non-PCD non-CF bronchiectasis or healthy subjects (median (range) 2.1 (1.3-3.5) ppb v 8.7 (4.5-26.0) ppb, p<0.001; 6.7 (2.6-11.9) ppb, p<0.001, respectively) but not lower than bronchiectatic patients with CF (3.0 (1.5-7.5) ppb, p>0.05). Nasal levels of nNO were significantly lower in PCD patients than in any other subjects (PCD: 54.5 (5.0-269) ppb, non-PCD bronchiectasis without CF: 680 (310-1000) ppb, non-PCD bronchiectasis with CF: 343 (30-997) ppb, control: 663 (322-1343) ppb). In contrast, eCO levels were higher in all patient groups than in control subjects (PCD: 4.5 (3.0-24.0) ppm, p<0.01, other bronchiectasis without CF: 5.0 (3.0-15.0) ppm, p<0.001; CF: 5.3 (2.0-23.0) ppm, p<0.001 v 3.0 (0.5-5.0) ppm). Low values in both eNO and nNO readings (<2.4 ppb and <187 ppb, respectively) identified PCD patients from other bronchiectatic patients with a specificity of 98% and a positive predictive value of 92%.ConclusionThe simultaneous measurement of eNO and nNO is a useful screening tool for PCD.

| S-EPMC1746449 | biostudies-literature

Nitric oxide hinders club cell proliferation through Gdpd2 during allergic airway inflammation.

Project description:Excessive nitric oxide (NO) is often observed in the airways of patients with severe asthma. Here, we show that the NO donor diethylamine NONOate impairs the proliferative capacity of mouse club cells and induces club cell apoptosis, cell cycle arrest, and alterations in lipid metabolism. Our data suggest that NO inhibits club cell proliferation via upregulation of Gdpd2 (glycerophosphodiester phosphodiesterase domain containing 2). During ovalbumin (OVA) challenge, apoptotic club cells are observed, but surviving club cells continue to proliferate. OVA exposure induces Gdpd2 expression; Gdpd2 knockout promotes the proliferation of club cells but inhibits goblet cell differentiation. Elimination of airway NO was found to inhibit goblet cell differentiation from club cells during OVA challenge. Our data reveal that excessive NO might be related to airway epithelial damage in severe asthma and suggest that blockade of the NO-Gdpd2 pathway may be beneficial for airway epithelial restoration.

| S-EPMC10240343 | biostudies-literature

A common variant in RAB27A gene is associated with fractional exhaled nitric oxide levels in adults.

Project description:Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics.We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations.We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium.We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values.This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.

| S-EPMC4405185 | biostudies-literature

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