Genetic modifiers of asthma response to air pollution in children: An African ancestry GWAS and PM_2.5 polygenic risk score study

Rationale: Ambient air pollution (AAP) is linked to asthma outcomes, but predicting individual risk remains challenging. Understanding genetic contributors to AAP sensitivity may help overcome this gap.

Objectives: To determine if single nucleotide polymorphisms (SNPs) are associated with AAP sensitivity in children with asthma.

Methods: We complete a GWAS in pediatric patients with asthma frequently exposed to AAP, comparing patients with exacerbations following spikes in AAP to patients without this temporal association and calculate a polygenic risk score (PRS) for PM_2.5. This PRS was validated using internal data and data from the All of Us cohort.

Measurements and results: We included 6023 patients in the GWAS, restricted to the African ancestry cohort due to the association between AAP exposure and race. Three loci reached genome-wide significance, including rs111970601, associated with CO sensitivity (odds ratio [OR] 6.58; P = 1.63 × 10^-8) and rs9836522 with PM_2.5 sensitivity (OR 0.75; P = 3,87 × 10^-9), both externally validated. PRS z-scores were associated with increased asthma exacerbations in patients frequently exposed to poor air quality (β = 0.15; P = 2.67 × 10⁻⁵). Spirometry data from 4138 patients showed that having a high PRS was associated with lower FVC z-scores in patients frequently exposed to AAP (β = -0.44; P = 0.035). External validation confirmed a significant interaction between high PRS and frequent AAP exposure (β = 0.30; P = 0.012) CONCLUSIONS: We associate specific SNPs with AAP-related asthma exacerbations and introduce a PM_2.5 sensitivity PRS, paving the way for future research aimed at protecting genetically predisposed patients.