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

Brown, Sara J., Asai, Yuka, Cordell, Heather, Campbell, Linda E., Zhao, Yiwei, Liao, Haihui, Northstone, Kate, Henderson, John, Alizadehfar, Reza, Ben-Shoshan, Moshe, Morgan, Kenneth, Roberts, Graham, Masthoff, Laury J.N., Pasmans, Suzanne G., van den Akker, Peter C., Wijmenga, Cisca, Hourihane, Jonathan O'B., Palmer, Colin N.A., Lack, Gideon, Clarke, Ann, Hull, Peter R., Irvine, Alan D. and McLean, W.H. Irwin (2011) Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. Journal of Allergy and Clinical Immunology, 127 (3), 661-667. (doi:10.1016/j.jaci.2011.01.031). (PMID:21377035)

Abstract

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 × 10?6; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 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.

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Contributors

Author: Graham Roberts

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