Uncovering the genetic variation involved in asthma exacerbations through multiple genomic approaches

Abstract

Asthma exacerbations are episodes of symptoms worsening that require urgent intervention to prevent a serious outcome. These usually involve unexpected asthma care, hospitalizations and/or oral corticosteroids use, and are influenced by a complex interplay of genetic, environmental, and behavioural factors. Due to the clinical and socio-economic burden of asthma exacerbations, there is a critical need to establish potential biomarkers to guide prevention. This doctoral thesis aimed to identify genetic variants involved in asthma exacerbations through multiple genomic approaches. A literature search for previous genetic associations for asthma exacerbations was conducted in order to detect relevant loci to validate in independent populations with different ancestral backgrounds. Moreover, in order to explore genetic variation on six genomic regions harbouring genes whose combined sputum gene expression had been previously shown to predict asthma exacerbations, a candidate-gene association study of asthma exacerbations was conducted. Additionally, a genome-wide association study of asthma with severe exacerbations in ethnically diverse children and youth and a multi-ancestry meta-analysis of genome-wide association studies of asthma exacerbations revealed three novel genetic loci implicated in asthma exacerbations. Likewise, the exploration of genomic variation by leveraging local ancestry in a context of admixed populations with differential asthma exacerbations rates uncovered two genetic loci for severe asthma exacerbations that may exert ethnic-specific effects. Finally, the functional effects of the genetic variation on DNA methylation and gene expression were investigated using public online data bases and whole-blood data from ethnically diverse populations. Our findings provided insights into the pathogenesis of asthma exacerbations and prioritised potential targets of research.

Asthma exacerbations are episodes of symptoms worsening (i.e., dysnea, cough, wheezing or chest tightness) that require urgent intervention to prevent a serious outcome. These usually involve unexpected asthma care, hospitalizations and/or oral corticosteroids use, and are influenced by a complex interplay of genetic, environmental, and behavioural factors. Due to the clinical and socio-economic burden of asthma exacerbations, there is a critical need to establish potential biomarkers to guide prevention. This doctoral thesis aimed to identify genetic variants involved in asthma exacerbations through multiple genomic approaches. A literature search for previous genetic associations for asthma exacerbations was conducted in order to detect relevant loci to validate in independent populations with different ancestral backgrounds. Moreover, in order to explore genetic variation on six genomic regions harbouring genes whose combined sputum gene expression had been previously shown to predict asthma exacerbations, a candidate-gene association study of asthma exacerbations was conducted. Additionally, a genome-wide association study of asthma with severe exacerbations in ethnically diverse children and youth and a multi-ancestry meta-analysis of genome-wide association studies of asthma exacerbations revealed three novel genetic loci implicated in asthma exacerbations. Likewise, the exploration of genomic variation by leveraging local ancestry in a context of admixed populations with differential asthma exacerbations rates uncovered two genetic loci for severe asthma exacerbations that may exert ethnic-specific effects. Finally, the functional effects of the genetic variation on DNA methylation and gene expression were investigated using public online data bases and whole-blood data from ethnically diverse populations. Our findings provided insights into the pathogenesis of asthma exacerbations and prioritised potential targets of research moving forward precision medicine, including the DNASE1L3, LINC01913, PKDCC, EXTL2, PANK1, DPYSL3, and SCGB3A2 genes.