Genome-wide Association Analysis Identifies Variants in the Chromosome 21 Associated with Asthma Exacerbations in Brazilian Adults

Introduction: Asthma exacerbations may cause mortality in asthma patients. This worsening of respiratory symptoms can be partially explained by genetic variability. Aims: To identify genetic variants associated with asthma exacerbations in patients with mild, moderate and severe asthma and to assess their functional role in epigenetics. Methods: A GWAS of asthma exacerbations was performed in 749 Brazilians of the ProAR study (mean age 43, 20% males, 55% with exacerbations) and 11 million genetic variants. Exacerbation was definded as use of systemic corticosteroids ≥ 3 days and/or emergency room visit and/or hospital admission in the last year. The analysis was adjusted for age, sex, asthma severity and principal components. Epigenetic effect was evaluated in silico using PhenoScanner v2. Results: The intergenic variants G allele of rs55670125, G allele of rs10854420, C allele of rs68160941, A allele of rs11910414 and A allele of rs35834033 were in linkage disequilibrium and reached genome wide significance with asthma exacerbations (OR: 2.5; p-value: 3.47e-8). These variants are located between the CXADR (coxsackieviruses and adenoviruses receptor) and LOC105372741 genes at chromosome 21. Asthma exacerbations are most commonly triggered by viral respiratory infections. Four of the identified SNVs were associated with histone modification of H3K4me1, wich has been previously linked to asthma pathogenesis. Conclusions: This GWAS disclosed a novel susceptibility locus for asthma exacerbations located at chromosome 21 that exhibited evidence of functional effects. The next steps are to replicate these findings in other populations. Fundings: CAPES