Chromosome 21 variants tied to severe asthma exacerbations: A genome-wide association study in a Brazilian population

Background: Asthma exacerbations are episodes of symptom worsening requiring increased therapy, which affect patients across all asthma severities. Potential genetic associations with asthma exacerbations in an understudied population were investigated. Objective: We sought to perform a genome-wide association study on severe asthma exacerbations in an admixed adult population with varying asthma severities and to explore potential epigenetic roles. Methods: A genome-wide association study was conducted in 727 Brazilian patients (mean age, 43 years; 20% male; and 55% with exacerbations) from the Programa de Controle da Asma na Bahia study, analyzing 12 million variants. Severe exacerbation was defined as systemic corticosteroid use for 3 or more days, emergency room visits, or hospital admissions within the past year. Analyses were adjusted for age, sex, asthma severity, and genotype principal components. Replication was sought in the cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (UBIOPRED) study, the Genes-environments and Admixture in Latino Americans II study, and the Study of African Americans, Asthma, Genes, and Environments using the same methodology. Epigenetic effects were assessed in silico via PhenoScanner v2. Results: Five intergenic variants (rs55670125, rs10854420, rs68160941, rs11910414, and rs35834033) in complete linkage disequilibrium reached genome-wide significance (odds ratio [OR], 2.5; P = 3.47 × 10−8), located between the CXADR and LOC105372741 genes on chromosome 21. Although not replicated, rs35834033 showed a nonsignificant trend (OR, 1.79; P = .17). Four variants were associated with H3K4me1 histone modification, linked to asthma pathogenesis. In addition, 88 suggestive variants were found; rs17697822 in FOXP1 was negatively associated with exacerbations (OR, 0.44; P = 4.03 × 10−6). Conclusions: The CXADR is highlighted as a potential novel susceptibility locus for asthma exacerbations, possibly tied to viral respiratory infections. Further replication and validation are needed.