Genetic modifiers of asthma response to air pollution in children: An African ancestry GWAS and PM 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. 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) and rs9836522 with PM sensitivity (OR 0.75; P = 3,87 × 10), 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 sensitivity PRS, paving the way for future research aimed at protecting genetically predisposed patients.