HLA-associated outcomes in peanut oral immunotherapy trials identify mechanistic and clinical determinants of therapeutic success.

Rationale: Previous studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission.

Methods: We determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-<48mo). We tested for association with remission, sustained unresponsiveness (SU), and desensitization in the OIT groups, as well as peanut component specific IgG4 (psIgG4) using generalized linear models and adjusting for relevant covariates and ancestry.

Results: While not quite statistically significant, a higher proportion of HLA-DQA1*01:02 carriers receiving OIT in IMPACT were desensitized (93%) compared to non-carriers (78%); odds ratio (OR)=5.74 (p=0.06). In this sample we also observed that a higher proportion of carriers achieved remission (35%) compared to non-carriers (22%); OR=1.26 (p=0.80). In POISED, carriers more frequently attained continued desensitization (80% versus 61% among non-carriers; OR=1.28, p=0.86) and achieved SU (52% versus 31%; OR=2.32, p=0.19). psIgG4 associations with HLA-DQA1*01:02 in the OIT arm of IMPACT which included younger study subjects recapitulated patterns noted in LEAP, but no associations of note were observed in the older POISED study subjects.

Conclusions: Findings across three clinical trials show a pattern of a gene environment interaction between HLA and oral peanut exposure. Age, and prior sensitization contribute additional determinants of outcomes, consistent with a mechanism of restricted antigen recognition fundamental to driving protective immune responses to OIT.