Genetic Determinants of Peanut‐Specific <scp>IgG4</scp> Levels in the Context of Sustained Oral Peanut Exposure in the <scp>LEAP</scp> Study

In the Learning Early About Peanut Allergy (LEAP) study, participants in the peanut consumption group, at 60 months of age, had higher levels of peanut-specific IgG4 (psIgG4), a biomarker of immune modulation, compared to those in the peanut-avoidance group. We investigated the genetic determinants of psIgG4 among participants who consumed peanuts. Using whole-genome sequencing data, we performed a genome-wide association study (GWAS) for psIgG4 in the LEAP peanut consumption group participants (N = 267). We generated a cumulative genetic score from the identified loci and evaluated its association with psIgG4 levels in LEAP. The association was then assessed for replication in two independent peanut oral immunotherapy (PnOIT) trials, IMPACT and POISED. We identified 45 variants that reached suggestive significance (p < 1 × 10^-5), mapping to 17 independent loci in the LEAP peanut consumption group; none of these variants were associated with the psIgG4 levels in the avoidance group, highlighting a potential gene-by-environment (GxE) interaction. One locus on chromosome 2 showed regulatory signatures for SEPT2, a gene involved in epithelial barrier function. The genetic score was significantly associated with psIgG4 among LEAP consumers (β = 0.433; p = 1.20 × 10^-58) in the discovery cohort and IMPACT PnOIT participants (β = 0.287; p = 0.02) in an independent testing cohort. No association was observed in older POISED PnOIT participants (β = -0.029; p = 0.79). Identification of the SEPT2 locus in participants protected from peanut allergy (PA) suggests involvement of epithelial barrier pathways in modulating immune responses. Findings across all three trials emphasise the importance of GxE interactions, specifically the interplay between genetics and oral peanut exposure. Taken together, the findings indicate that early, sustained peanut consumption, combined with genetic factors, promotes a protective immune response to peanut allergens. Trial Registration: LEAP: NCT00329784; IMPACT: NCT03345160; POISED, NCT02103270.