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Eczema in causal pathway between IL4RA variant and food allergy

Published: May 16, 2022

Food allergy and (atopic) eczema may share genetic risk factors, however, it is unknown whether genetic factors directly cause food allergy or are mediated through eczema. The dual-allergen exposure hypothesis suggests that early consumption of food proteins induces oral tolerance, offering protection against development of food allergies, while allergic sensitization to food can occur through the skin. Studies have described an increased risk of peanut sensitization and clinically confirmed peanut allergy due to epicutaneous exposure to peanut through an impaired skin barrier.

In an original article published in The Journal of Allergy and Clinical Immunology: In Practice, Banzon and Kelly et al. found that in a cohort of school-aged children with asthma, eczema is part of the causal pathway between a human interleukin-4 receptor alpha gene variant (IL4RA) and food allergy. This IL4RA variant has been identified as a possible locus of genetic predisposition for atopic disease, including asthma diagnosis and severity, and results in a glutamine to arginine substitution at amino acid residue 576 (IL4Rα-R576 polymorphism).

To test the hypothesis that eczema mediates the relationship between this IL4RA variant and food allergy, 433 children enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA allele, with physician diagnosis of food allergy, eczema, and associated allergic responses. The authors performed causal mediation analysis, and adjusted for age, race and ethnicity, gender, and household income.

The authors found that each risk allele increased the odds of eczema, and eczema increased the odds of food allergy. They described an indirect effect of genotype, which was mediated by eczema, predicting food allergy. This suggests that eczema is part of the causal pathway between a common IL4RA polymorphism and food allergy, where a dose-response relationship between number of risk alleles and patient-reported severe food allergy reaction was found. Since a person’s genotype is fixed and unalterable, the work suggests that interventions targeted towards eczema can influence food allergy diagnosis in children born with the risk allele and lends support to the dual-allergen hypothesis. Their work also provides support for several ongoing trials using IL-4 monoclonal antibodies in treatment for atopic diseases in general, but specifically for those with IL4RA polymorphisms and with both eczema and food allergy. The authors recommended that further work is necessary in understanding disease modifying treatments for eczema which may concurrently decrease risk for future development of food allergy in children with genetic risk factors, thus empowering clinicians to take a more personalized medicine approach in identifying and caring for patients at-risk for developing food allergy or having severe food allergy reactions.

The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.

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