Genome-Wide Association Study of Fluorescent Oxidation Products Accounting for Tobacco Smoking Status in Adults from the French EGEA Study.

Oxidative stress (OS) is the main pathophysiological mechanism involved in several chronic diseases, including asthma. Fluorescent oxidation products (FlOPs), a global biomarker of damage due to OS, is of growing interest in epidemiological studies. We conducted a genome-wide association study (GWAS) of the FlOPs level in 1216 adults from the case-control and family-based EGEA study (mean age 43 years old, 51% women, and 23% current smokers) to identify genetic variants associated with FlOPs. The GWAS was first conducted in the whole sample and then stratified according to smoking status, the main exogenous source of reactive oxygen species. Among the top genetic variants identified by the three GWAS, those located in BMP6 (p = 3 × 10-6), near BMPER (p = 9 × 10-6), in GABRG3 (p = 4 × 10-7), and near ATG5 (p = 2 × 10-9) are the most relevant because of both their link to biological pathways related to OS and their association with several chronic diseases for which the role of OS in their pathophysiology has been pointed out. BMP6 and BMPER are of particular interest due to their involvement in the same biological pathways related to OS and their functional interaction. To conclude, this study, which is the first GWAS of FlOPs, provides new insights into the pathophysiology of chronic OS-related diseases.

Association between occupational exposure to irritant agents and a distinct asthma endotype in adults.

AIM: The biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and current asthmatics (CA) integrating clinical characteristics and biomarkers related to oxidative stress and inflammation. METHODS: We used cross-sectional data from 999 adults (mean 45 years old, 46% men) from the case-control and familial Epidemiological study on the Genetics and Environments of Asthma (EGEA) study. Five respiratory endotypes have been identified using a cluster-based approach: NA1 (n=463) asymptomatic, NA2 (n=169) with respiratory symptoms, CA1 (n=50) with active treated adult-onset asthma, poor lung function, high blood neutrophil counts and high fluorescent oxidation products level, CA2 (n=203) with mild middle-age asthma, rhinitis and low immunoglobulin E level, and CA3 (n=114) with inactive/mild untreated allergic childhood-onset asthma. Occupational exposure to irritants during the current or last held job was assessed by the updated occupational asthma-specific job-exposure matrix (levels of exposure: no/medium/high). Associations between irritants and each respiratory endotype (NA1 asymptomatic as reference) were studied using logistic regressions adjusted for age, sex and smoking status. RESULTS: Prevalence of high occupational exposure to irritants was 7% in NA1, 6% in NA2, 16% in CA1, 7% in CA2 and 10% in CA3. High exposure to irritants was associated with CA1 (adjusted OR aOR, (95% CI) 2.7 (1.0 to 7.3)). Exposure to irritants was not significantly associated with other endotypes (aOR range: 0.8 to 1.5). CONCLUSION: Occupational exposure to irritants was associated with a distinct respiratory endotype suggesting oxidative stress and neutrophilic inflammation as potential associated biological mechanisms.

PID1 is associated to a respiratory endotype related to occupational exposures to irritants.

BACKGROUND: Studying associations between genes and asthma endotypes and interactions with environment could help to identify new susceptibility genes. We used a previously identified asthma endotype characterized by adult-onset asthma, poor lung function, and high level of Fluorescent oxidation products, a marker of damages due to oxidative stress. This endotype was associated with high occupational exposure to irritants. We aimed to investigate the associations between genes related to oxidative stress and this endotype, and if the associations differed according to irritants exposure. METHODS: We conducted association analyses between the asthma endotype and genetic variants (4715 SNPs) located in 422 genes involved in the "response to oxidative stress" in adults from the Epidemiological study on the Genetic and Environment of Asthma. Analyses using logistic regression were conducted first in all participants, and then separately among high vs. non-exposed participants to assess whether association differs according to irritants exposure. RESULTS: An association was found between the SNP rs1419958 located in PID1 gene and the endotype (P = 2.2E-05), reaching significance level after correction for multiple testing. This association was even more significant in non-exposed participants (P = 1.06E-06) while there was no association in participants with high exposure to occupational irritants. CONCLUSION: This study showed a significant association between an asthma endotype and PID1, a promising candidate gene, the association being different according to the exposure to irritants. These results highlight the interest of studying asthma endotypes in association with genes from candidate pathways and their link with occupational irritants to decipher asthma etiology.

Endotypes identified by cluster analysis in asthmatics and non-asthmatics and their clinical characteristics at follow-up: the case-control EGEA study.

BACKGROUND: Identifying relevant asthma endotypes may be the first step towards improving asthma management. We aimed identifying respiratory endotypes in adults using a cluster analysis and to compare their clinical characteristics at follow-up. METHODS: The analysis was performed separately among current asthmatics (CA, n=402) and never asthmatics (NA, n=666) from the first follow-up of the French EGEA study (EGEA2). Cluster analysis jointly considered 4 demographic, 22 clinical/functional (respiratory symptoms, asthma treatments, lung function) and four blood biological (allergy-related, inflammation-related and oxidative stress-related biomarkers) characteristics at EGEA2. The clinical characteristics at follow-up (EGEA3) were compared according to the endotype identified at EGEA2. RESULTS: We identified five respiratory endotypes, three among CA and two among NA: CA1 (n=53) with active treated adult-onset asthma, poor lung function, chronic cough and phlegm and dyspnoea, high body mass index, and high blood neutrophil count and fluorescent oxidation products level; CA2 (n=219) with mild asthma and rhinitis; CA3 (n=130) with inactive/mild untreated allergic childhood-onset asthma, high frequency of current smokers and low frequency of attacks of breathlessness at rest, and high IgE level; NA1 (n=489) asymptomatic, and NA2 (n=177) with respiratory symptoms, high blood neutrophil and eosinophil counts. CA1 had poor asthma control and high leptin level, CA2 had hyper-responsiveness and high interleukin (IL)-1Ra, IL-5, IL-7, IL-8, IL-10, IL-13 and TNF-α levels, and NA2 had high leptin and C reactive protein levels. Ten years later, asthmatics in CA1 had worse clinical characteristics whereas those in CA3 had better respiratory outcomes than CA2; NA in NA2 had more respiratory symptoms and higher rate of incident asthma than those in NA1. CONCLUSION: These results highlight the interest to jointly consider clinical and biological characteristics in cluster analyses to identify endotypes among adults with or without asthma.

High level of fluorescent oxidation products and worsening of asthma control over time.

High Fluorescent oxidation products level (FlOPs), a global oxidative stress biomarker, was associated cross-sectionally with poor asthma outcomes but its longitudinal association with asthma evolution has never been examined. We aimed to study the associations between FlOPs level at baseline and changes in current asthma, asthma attacks and asthma control status over 8 years. We used data from the second survey of the French EGEA cohort study as baseline and the third survey as follow-up. At baseline, the mean age of the 489 participants with ever asthma was 39 (± 16) years, 49% were women. Among participants with controlled asthma at baseline, high FlOPs level was significantly associated with worsening of asthma control at follow-up (odds-ratio adjusted for age, sex and smoking status (95% CI): 2.27 (1.32-3.90). No other significant associations were observed. In conclusion, results suggest FlOPs as a predictor of asthma evolution in adults and a good candidate marker in asthma management.

Oxidative stress biomarkers and asthma characteristics in adults of the EGEA study.

Asthma is an oxidative stress related disease, but associations with asthma outcomes are poorly studied in adults. We aimed to study the associations between several biomarkers related to oxidative stress and various asthma outcomes.Cross-sectional analyses were conducted in 1388 adults (mean age 43 years, 44% with asthma) from the Epidemiological Study of the Genetics and Environment of Asthma (EGEA2). Three blood antioxidant enzyme activities (biomarkers of response to oxidative stress) and exhaled breath condensate 8-isoprostanes and plasma fluorescent oxidation products (FlOPs) levels (two biomarkers of damage) were measured. Associations between biomarkers and 1) ever asthma and 2) asthma attacks, asthma control and lung function in participants with asthma were evaluated using regression models adjusted for age, sex and smoking.Biomarkers of response were unrelated to asthma outcomes. Higher 8-isoprostane levels were significantly associated with ever asthma (odds ratio for one interquartile range increase 1.28 (95% CI 1.06-1.67). Among participants with asthma, 8-isoprostane levels were negatively associated with adult-onset asthma (0.63, 0.41-0.97) and FlOPs levels were positively associated with asthma attacks (1.33, 1.07-1.65), poor asthma control (1.30, 1.02-1.66) and poor lung function (1.34, 1.04-1.74).Our results suggest that 8-isoprostanes are involved in childhood-onset asthma and FlOPs are linked to asthma expression.

Introduction of rubella-containing-vaccine to Madagascar: implications for roll-out and local elimination.

Few countries in Africa currently include rubella-containing vaccination (RCV) in their immunization schedule. The Global Alliance for Vaccines Initiative (GAVI) recently opened a funding window that has motivated more widespread roll-out of RCV. As countries plan RCV introductions, an understanding of the existing burden, spatial patterns of vaccine coverage, and the impact of patterns of local extinction and reintroduction for rubella will be critical to developing effective programmes. As one of the first countries proposing RCV introduction in part with GAVI funding, Madagascar provides a powerful and timely case study. We analyse serological data from measles surveillance systems to characterize the epidemiology of rubella in Madagascar. Combining these results with data on measles vaccination delivery, we develop an age-structured model to simulate rubella vaccination scenarios and evaluate the dynamics of rubella and the burden of congenital rubella syndrome (CRS) across Madagascar. We additionally evaluate the drivers of spatial heterogeneity in age of infection to identify focal locations where vaccine surveillance should be strengthened and where challenges to successful vaccination introduction are expected. Our analyses indicate that characteristics of rubella in Madagascar are in line with global observations, with an average age of infection near 7 years, and an impact of frequent local extinction with reintroductions causing localized epidemics. Modelling results indicate that introduction of RCV into the routine programme alone may initially decrease rubella incidence but then result in cumulative increases in the burden of CRS in some regions (and transient increases in this burden in many regions). Deployment of RCV with regular supplementary campaigns will mitigate these outcomes. Results suggest that introduction of RCV offers a potential for elimination of rubella in Madagascar, but also emphasize both that targeted vaccination is likely to be a lynchpin of this success, and the public health vigilance that this introduction will require.