323 - Polygenic Asthma Risk Scores Were Not Associated with Early-Life Wheezing: preliminary data from the IDEAL Rome Cohort.

Publication Number: 2312.323

David Martino, Kids Research Institute Australia, Nedlands, Western Australia, Australia; Joann Diray-Arce, Boston Children's Hospital, Boston, MA, United States; Annmarie Hoch, Boston Children's Hospital, Cambridge, MA, United States; Kerry McEnaney, Boston Children's Hospital, Boston, MA, United States; Marco Sanna, Ospedale Pediatrico Bambino Gesù, Roma, Lazio, Italy; Jessica A. Lasky-Su, Brigham and Women's Hospital, Bston, MA, United States; Ofer Levy, Precision Vaccines Program, Boston Children's Hospital, Boston, MA, United States

Background: The genetic contribution to early-life wheezing remains unclear. While wheezing in infancy often precedes asthma, it is also frequently triggered by viral infections and may not share the same genetic architecture.

Objective: We investigated whether polygenic risk for childhood onset asthma predicts wheezing episodes in early childhood.

Design/Methods: We analysed 131 infants out of 273 (1,061 longitudinal visits) from the IDEAL longitudinal birth cohort based in Rome, Italy with linked genotype and detailed clinical phenotyping. Pediatric asthma polygenic risk scores (PRS; PGS002248) were computed using genome-wide SNP data and ancestry-adjusted. High-risk status was defined as ≥82nd percentile (≥2× population risk). Clinical outcomes included cumulative wheezing episodes, wheezing proneness (≥3 episodes by age 1 or 2 years), and recurrent infections. Linear mixed models assessed associations between PRS, age, and outcomes, adjusting for sex and repeated measures. Mediation analysis tested whether infection frequency might mediate PRS effects on wheeze.

Results: PRS did not predict cumulative wheezing episodes (β = 0.08 ± 0.18, p = 0.42). Age significantly predicted wheeze (β = 0.06 ± 0.004, p < 0.001), and males had higher wheeze burden (β = 0.55 ± 0.22, p = 0.02). Higher PRS was associated with fewer infections (β = –0.19 ± 0.08, p = 0.02). Mediation analysis showed no significant indirect pathway through infection burden (ACME = –0.10, 95% CI –0.39 to 0.07, p = 0.31). The total effect of PRS on wheeze was non-significant (β = –0.60, p = 0.12).

Conclusion(s): Asthma polygenic risk did not predict early-life wheezing, raising the possibility that infant wheeze is primarily infection-driven. The modest inverse relationship between PRS and infection frequency suggests that genetic asthma risk may exert minimal influence until later childhood when immune and atopic pathways dominate.