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

ABSTRACT: 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.

SUBMITTER: Bouzigon E

PROVIDER: S-EPMC4405185 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Bouzigon E E Nadif R R Thompson E E EE Concas M P MP Kuldanek S S Du G G Brossard M M Lavielle N N Sarnowski C C Vaysse A A Dessen P P van der Valk R J P RJ Duijts L L Henderson A J AJ Jaddoe V W V VW de Jongste J C JC Casula S S Biino G G Dizier M-H MH Pin I I Matran R R Lathrop M M Pirastu M M Demenais F F Ober C C

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 20150401 4

<h4>Background</h4>Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics.<h4>Objective</h4>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.<h4>Methods</h4>We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery ...[more]

PMID: 25431337

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Project description:ObjectiveAirway inflammation plays an important role in obstructive sleep apnea (OSA); exhaled nitric oxide is regarded as a noninvasive marker of airway inflammation. The aim of this study was to evaluate fractional exhaled nitric oxide (FeNO) and nasal nitric oxide (nNO) in patients with OSA.MethodsSeventy-five patients with OSA and 30 health controls were enrolled in this study. FeNO and nNO were measured before and after sleep. Nasal lavage was performed in 31 non-smoking individuals immediately after NO measurement in the morning. The sample of nasal lavage was taken for cell classification and analyzing interleukin 6 (IL-6) and interleukin 8 (IL-8).ResultsBoth FeNO and nNO were significantly higher in OSA (before sleep FeNO 21.08 ± 8.79 ppb vs.16.90 ± 6.86 ppb, p = 0.022; after sleep FeNO 25.57 ± 15.58 ppb vs.18.07 ± 6.25 ppb, p = 0.003; before sleep nNO 487.03 ± 115.83 ppb vs. 413.37 ± 73.10 ppb, p = 0.001; after sleep nNO 550.07 ± 130.24 ppb vs. 460.43 ± 109.77 ppb, p < 0.001). Furthermore, in non-smoking OSA, nNO levels were positively correlated with apnea hypopnea index (AHI) and average decrease of pulse arterial oxygen saturation (SpO2); after sleep, nNO was also positively associated to recording time with SpO2 < 90% and negatively associated to minimum SpO2. Both before and after sleep nNO levels were positively correlated with the percentage of neutrophils in nasal lavage (r = 0.528, p = 0.014; r = 0.702, p < 0.001, respectively). Additionally, before sleep nNO was also positively associated with IL-6 (r = 0.586, p = 0.005) and IL-8 (r = 0.520, p = 0.016) concentration.ConclusionThis study sustains the presence of airway inflammation in OSA patients with the increase of FeNO and nNO. The data suggests nNO might have greater value than FeNO since it positively correlated with OSA severity, and nNO is a potential bio-marker of nasal inflammation in non-smoking OSA patients.

Project description:Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker of respiratory tract inflammation, originally designated to identify eosinophilic airway inflammation and to predict steroid response. The main field of application of this biomarker is asthma, but FeNO has also been used for other allergic and non-allergic pulmonary disorders such as chronic obstructive pulmonary disease, hypersensitivity pneumonitis and interstitial lung disease. A substantial part of respiratory diseases are related to work, and FeNO, a safe and easy measure to conduct, is a potential valid examination in an occupational setting.This systematic review assesses the value of measuring FeNO related to three types of airborne exposures: allergens, irritants, and respiratory particles inhaled during occupational activities. The review covers results from longitudinal and observational clinical studies, and highlights the added value of this biomarker in monitoring effects of exposure and in the diagnostic criteria of occupational diseases. This review also covers the possible significance of FeNO as an indicator of the efficacy of interventions to prevent work-related respiratory diseases.Initially, 246 articles were identified in PUBMED and SCOPUS. Duplicates and articles which covered results from the general population, symptoms (not disease) related to work, non-occupational diseases, and case reports were excluded. Finally, 39 articles contributed to this review, which led to the following conclusions:a) For occupational asthma there is no consensus on the significant value of FeNO for diagnosis, or on the magnitude of change needed after specific inhalation test or occupational exposure at the workplace. There is some consensus for the optimal time to measure FeNO after exposure, mainly after 24 h, and FeNO proved to be more sensitive than spirometry in measuring the result of an intervention. b) For other occupational obstructive respiratory diseases, current data suggests performing the measurement after the work shift. c) For interstitial lung disease, the evaluation of the alveolar component of NO is probably the most suitable.

Dataset Information

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

Publications

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

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