HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy

Abstract Background Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients showed allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). Objectives The aim of the present study was to investigate genetic variation that may contribute to susceptibility to HWP allergy. Methods We conducted a genome-wide association study (GWAS) of HWP allergy in 452 cases and 2,700 controls using 6.6 million genotyped or imputed single-nucleotide polymorphisms (SNPs). Replication was assessed by genotyping SNPs in independent samples comprising 45 HWP allergic patients and 326 controls. Results Through the GWAS, we identified significant associations with the class II human leukocyte antigen (HLA) region on 6p21 ( P = 2.16 × 10 -24 for rs9271588, P = 2.96 × 10 -24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10 -9 ). The associations were also confirmed in the replication dataset. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA DQ molecule achieved the genome-wide significance level ( P -8 ). Conclusions Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.