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Asthma is a chronic inflammatory disease of the airways characterized by reversible airflow obstruction and an exaggerated bronchial response to a wide variety of stimuli. In most patients, asthma symptoms can be controlled. However, many may experience asthma attacks or crises called exacerbations, which are characterized by shortness of breath, wheezing, coughing, or chest tightness, and can become life-threatening. These exacerbations are caused by a combination of environmental and genetic factors. However, only a limited number of genes are known to be associated with a predisposition to these complications, as studies to date have been limited. Furthermore, some recent studies have used massive sequencing techniques to characterize the airway microbiome (i.e., the community of microorganisms), finding changes related to asthma. Despite this, no study has focused on analyzing the microbiome of patients with exacerbations. The main hypothesis of this project is that asthma exacerbations are caused by a combination of intrinsic genetic factors, changes in the respiratory microbiome, and the interaction between these two components. The objectives of this research project are: 1) to identify genetic variants associated with the occurrence of asthma exacerbations; 2) to examine the changes that occur in the microbial communities of the oral cavity and respiratory tract in individuals experiencing exacerbations; and 3) to analyze the association between genetic variants present in individuals and microbiome changes associated with asthma exacerbations. For the first objective, the largest genomic study of asthma exacerbations to date will be conducted, analyzing a total of 10,181 individuals from diverse populations, both with and without exacerbations, belonging to national and international cohorts. The data will be analyzed together using different approaches (genomic association studies of millions of variants, integration of data into biological processes, and mixture mapping), and the results will be validated in an additional 3,886 samples from independent studies. The second and third objectives address novel aspects in the context of the genomics and metagenomics of asthma exacerbations. Three hundred adult Spanish asthmatic patients will be analyzed: 150 will have controlled asthma, and 150 will experience exacerbations at the time of inclusion. Massive sequencing of a specific marker will be performed in these patients to characterize bacterial diversity and abundance, as well as to infer microbiome function in samples from different sources (salivary, pharyngeal, and nasal). These measurements will be used to establish correlations between the microbiome and the presence of asthma exacerbations. Finally, the association between an individual's genetic variation and measures of microbiome abundance, diversity, and function associated with exacerbations will be analyzed. The results of this study are expected to have a major scientific and socioeconomic impact, contributing to a better understanding of the genetic and molecular mechanisms underlying the occurrence of asthma exacerbations.
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Asthma is a chronic inflammatory disease of the airways characterized by reversible airflow obstruction and a bronchial hyperreactivity in response to a variety of stimuli. In most patients, the onset of asthma symptoms may be controlled. However, many of them may manifest asthma attacks or crises of breathing called exacerbations, which occur with breathing problems, wheezing, coughing or tightness of chest, and may threaten their life. Such exacerbations are caused by a combination of environmental and genetic factors. However, since studies have been limited, a reduced number of genes associated with the predisposition to these complications have been identified. In addition, some studies have used next-generation DNA sequencing techniques to characterize the microbiome (ie, microbial community) of the airways, finding changes related to asthma. Despite this, not a single study has focused on the microbiome analysis of patients with exacerbations. The main hypothesis of this project is that exacerbations of asthma are caused by a combination of the intrinsic genetic factors of the individual, changes in the respiratory microbiome and the interaction between both factors. The objectives of this project are: 1) to identify genetic variants that are associated with asthma exacerbations; 2) to examine the changes occurring in the microbial communities of the oral cavity and respiratory tract in individuals with exacerbations; 3) to analyze the association of the host genetic variants and the microbiome changes related to exacerbations. The first aim represents the largest genomic study of asthma exacerbations performed to date, including a total of 10,181 individuals from diverse populations with and without exacerbations from different national and international cohorts. Integrative data analysis will be conducted by using different approaches (genomic association study of millions of variants, data integration in biological processes, and admixture mapping), and the results will be validated in another set of 3,886 samples from independent studies. In the second and third aim, novel aspects will be evaluated in the context of genomics and metagenomics of asthma exacerbations. A total of 300 Spanish adult asthmatic patients will be recruited: 150 with controlled asthma and 150 with exacerbations at the time of inclusion. In all of them, saliva, nasal and pharyngeal samples will be collected to study the oral cavity and the upper respiratory tract microbiome through next-generation sequencing technologies. Sequencing of a specific marker will allow to characterize the bacterial diversity and abundance, as well as to infer the functionality of the microbiome in each sample. These parameters will be used to establish correlations between the microbiome and the presence of asthma exacerbations. Finally, the association between the genetic variation and the measurements of abundance, diversity and functions related to exacerbations will be examined. The results of this study are expected to have a greater scientific and socioeconomic impact, contributing to a better understanding of the genetic and molecular mechanisms underlying the development of asthma exacerbations. [/vc_column_text][/vc_tta_section][/vc_tta_accordion][/vc_column][/vc_row]