Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Abstract

Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.

Associations between Milk and Egg Allergens and the HLA-DRB1/DQ Polymorphism: A Bioinformatics Approach

“…As peanut allergy is the most common, severe, usually permanent and increasingly prevalent food allergy, and is also associated with substantial morbidity and mortality [12], most studies looking for associations between the HLA polymorphism and food allergy focus on peanut allergy [13,14,15,16,17]. Less is known about the association between the HLA polymorphism and milk allergy.…”

The role of epigenetic mediation and the future of food allergy research

“…Further linking epigenetics and FA, the first genome-wide association study (GWAS) of FA in 2759 US participants revealed the important role of differential DNAm in mediating identified genetic risk factors for peanut allergies. [42]. Considering this direct evidential support and our current understanding of epigenetics, the study of epigenetics in FA is a promising avenue that may lead to a better understanding of the mechanisms underlying FA etiology.…”

“…We currently know very little about the role of epigenetics in FA, and only three studies provide direct evidence linking epigenetics and the disease [40][41][42]. Martino et al investigated whether variation in DNA methylation (DNAm) underscores the suboptimal neonatal CD4+ T-cell gene expression associated with the development of FA [40], including impaired T-cell expansion and reduced IFN-␥ production [43][44][45][46].…”

“…The first GWAS of a well-defined FA was performed in a US cohort of children and their biological parents [42]. The authors performed a three-stage GWAS looking for genetic associations with any FA particularly focused on milk, egg, and peanut allergies (PA).…”

The Implications of DNA Methylation on Food Allergy

“…The first genome-wide association study of well-defined food allergy was conducted in Chicago [30]. This study recruited 2,759 participants who were sensitized to peanut.…”