Self-reported health history from 70,724 individuals reveals novel HLA associations with allergy and other frequently underreported conditions.
Boquett Juliano André JA, Yu-Tseng Lin Sean S, House John S JS, Ahn Kwangmi K KK et al.
Variation in the HLA loci, located on human chromosome 6p, has been associated with hundreds of diseases and conditions. However, high levels of polymorphism that characterize the HLA system, coupled with generally modest effect sizes for most phenotypes, necessitate relatively large sample sizes to power association studies; meanwhile, high resolution HLA genotyping remains relatively resource intensive. These constraints limit identification of novel associations. While phenome-wide association studies (PheWAS) in the context of large registries with available electronic health records (EHR) have revealed new insights into the role of HLA in disease, many common health conditions are poorly represented in EHR due to the temporal nature of their occurrence or general underreporting. Further, these studies have generally been conducted with HLA genotyping data imputed from microarrays, rather than direct measurement of high-resolution genotypes. To overcome these limitations and reveal novel HLA associations we undertook a PheWAS in many previously understudied health conditions. We queried over 290 conditions, diseases and traits from 70,724 subjects registered with NMDP (formerly known as the National Marrow Donor Program) with available high-resolution HLA genotyping (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1). After stratifying according to self-reported geographic ancestry, we performed a logistic regression analysis adjusting for sex and age for HLA-phenotype association. We identified 48 significant HLA associations across self-reported geographic ancestry groups, confirming several known associations and uncovered fourteen novel associations. Most novel associations pertained to common infectious or allergic phenotypes that often go under-reported in the EHR. We identified a previously underappreciated yet very strong association between HLA-DRB1*04:01 and self-reported cefaclor adverse-reaction label of unverified mechanism (OR = 3.74, p-value 5.10E-28), which remained highly significant after excluding individuals reporting multiple drug hypersensitivities (OR = 3.13, p-value = 5.60E-15). Exploratory computational co-folding structure-and-affinity prediction identified a potential interaction between cefaclor and the P4 pocket of HLA-DRB1*04:01, providing a hypothesis-generating structural rationale that requires functional validation. If validated in independent cohorts with clinically characterized phenotypes and functional studies, this association may inform pharmacogenomic risk stratification and targeted prevention of adverse drug reactions. Other novel associations found, such as susceptibility to genital warts (HPV) and allergic rhinitis, reveal new insights into the role of specific HLA alleles in immune-mediated disease. Many of these novel associations were replicated in the independent All of Us cohort (AoU), while others showed the same trend for association, confirming the validity of this approach. Collectively, our findings demonstrate the value of integrating population-scale, high-resolution HLA genotypes with phenotyping beyond the EHR to reveal immunogenetic influences on common health outcomes. These findings motivate future functional studies and validation in clinically characterized cohorts to refine mechanistic understanding and determine potential clinical utility.