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Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Sara J SJ Brown, Yuka Y Asai, Heather J HJ Cordell, Linda E LE Campbell, Yiwei Y Zhao, Haihui H Liao, Kate K Northstone, John J Henderson, Reza R Alizadehfar, Moshe M Ben-Shoshan, Kenneth K Morgan, Graham G Roberts, Laury J N LJ Masthoff, Suzanne G M A SG Pasmans, Peter C PC van den Akker, Cisca C Wijmenga, Jonathan O'B JO Hourihane, Colin N A CN Palmer, Gideon G Lack, Ann A Clarke, Peter R PR Hull, Alan D AD Irvine, and W H Irwin WH McLean

J Allergy Clin Immunol 127(3):7 (2011) PMID 21377035 PMCID PMC3081065

Background: IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective: To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods: Case-control study of 71 English, Dutch, and Irish oral food challenge-positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut >=8 mm and/or peanut-specific IgE >=15 kUL^-^1) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results: Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge-positive patients (P = 3.0 x 10^-^6; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 x 10^-^5; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis. Conclusion: Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

Copyright © 2011 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.jaci.2011.01.031
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