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Food Allergy GWAS Leads to Five Susceptibility Loci

NEW YORK (GenomeWeb) - A German-led team has tracked down a handful of genetic loci with apparent ties to food allergy susceptibility, including an immune locus specifically implicated in peanut allergy and four loci with broader food allergy associations.

As they reported online today in Nature Communications, the researchers performed a genome-wide association study involving almost 500 German cases — individuals diagnosed with food allergies following an oral food challenge test — and nearly 2,400 unaffected controls. Their search led to five loci with significant food allergy associations, ranging from variants in immune and inflammatory genes to those falling in genes with epithelial barrier functions.

The team validated results from the discovery cohorts using genetic data for thousands of individuals with or without food allergies from Germany or the US, before digging into a chromosome 18 SERPINB gene cluster that had not been implicated in food allergy risk in past studies. Those experiments suggested food allergy-linked variants at that locus may impact everything from SERPINB10 gene expression in the blood to the regulation of inflammatory and immune genes.

"The discovery of the SERPINB gene cluster in food allergy susceptibility emphasizes the importance of proteolytic pathways in the regulation of the immune response and in the maintenance of the epithelial barrier, both of which are impaired in food allergy," senior author Young-Ae Lee, a researcher affiliated with the Max-Delbrück Center for Molecular Medicine and Charité University Medical Center's pediatric allergy clinic, and her colleagues wrote.

Past studies suggest that food allergies stem from both genetic and environmental contributors, the team noted, though prior searches for genetic contributors have typically focused on peanut allergy or on individuals with self-reported food allergies rather than diagnoses done with a food challenge.

"[I]n order to standardize the diagnostic criteria of food allergy, current guidelines recommend oral food challenges as the diagnostic gold standard for food allergy," the authors explained. Consequently, they focused their own GWAS on food allergy cases confirmed by oral food challenge, starting with 523 food allergy-affected and 2,682 food allergy-free individuals from Germany who were genotyped with Illumina arrays.

By comparing directly genotyped and imputed SNP profiles in the 497 cases and 2,387 controls remaining their quality control steps, the team identified suspicious SNPs that were subsequently scrutinized in 379 food allergy cases and 984 controls from Germany and a second replication cohort from the US comprised of 671 individuals with food allergy and 1,526 without.

Using this approach, the researchers uncovered genome-wide significant food allergy associations at five sites: the SERPINB gene cluster, a locus in and around a chromosome 5 cytokine gene cluster, a chromosome 1 locus encompassing the filaggrin epidermal barrier gene FLG, a C11orf30/LRRC32 locus on chromosome 11, and a chromosome 6 human leukocyte antigen (HLA) locus.

By looking at subsets of individuals with specific food allergy types — namely peanut allergy, hen's egg allergy, or cow's milk allergy — they found that the HLA association was specific to peanut allergy cases, while the remaining loci had apparent ties to food allergy in general. 

The authors noted that clade B serpins such as SERPINB10 "are involved in several biological functions, including protease inhibition, tumor suppression, regulation of apoptosis, and inflammation. Of note, many clade B serpins have very restricted expression patterns with high expression levels in the esophageal mucosa."