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

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.

Journal Title:	Journal of allergy and clinical immunology 2011, Vol.127 (3), p.661-667
Main Author:	Brown, Sara J., MD
Other Authors:	Asai, Yuka, MD , Cordell, Heather J., DPhil , Campbell, Linda E., MSc , Zhao, Yiwei, MD, PhD , Liao, Haihui, MD, PhD , Northstone, Kate, PhD , Henderson, John, MD , Alizadehfar, Reza, MD , Ben-Shoshan, Moshe, MD , Morgan, Kenneth, PhD , Roberts, Graham, DM , Masthoff, Laury J.N., MD , Pasmans, Suzanne G.M.A., MD, PhD , van den Akker, Peter C., MD , Wijmenga, Cisca, PhD , Hourihane, Jonathan O’B., PhD , Palmer, Colin N.A., PhD , Lack, Gideon, PhD , Clarke, Ann, MD, MSc , Hull, Peter R., MD, PhD , Irvine, Alan D., MD , McLean, W. H. Irwin, PhD, DSc
Format:	Electronic Article
Language:	English
Subjects:	AD, Atopic dermatitis Allergens Allergies Allergy Allergy and Immunology ALSPAC, Avon Longitudinal Study of Parents and Children Arachis hypogaea ASTHMA ATOPIC-DERMATITIS Avon Longitudinal Study of Parents beverages Canada Case-Control Studies CHILDHOOD CHILDREN Children & youth Dermatitis ECZEMA Etiology Europe Filaggrin Filaggrin Proteins FLG, Filaggrin food Food allergies Food allergy FOOD CHALLENGES Food hypersensitivity Genetic Association Studies Genetic engineering Genetic Predisposition to Disease Genetic research Genetic Variation Health aspects Heritability Humans Hypersensitivity Hypersensitivity, Immediate IgE Immunoglobulin E Immunology Intermediate Filament Proteins - genetics Ireland MANAGEMENT Medical colleges Mutation Netherlands Nuts Odds ratio OR, Odds ratio Peanut allergy Peanut Hypersensitivity - genetics Peanuts PREVALENCE PRICK Replication Respiratory agents risk factor Risk Factors SKIN BARRIER FUNCTION Skin prick test Skin tests Special section SPT, Skin prick test UK, United Kingdom UMCG Approved United Kingdom
Quelle:	Alma/SFX Local Collection
Publisher:	United States: Elsevier Inc
ID:	ISSN: 0091-6749
Link:	https://www.ncbi.nlm.nih.gov/pubmed/21377035
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title:	Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy
format:	Article
creator:	Brown, Sara J., MD Asai, Yuka, MD Cordell, Heather J., DPhil Campbell, Linda E., MSc Zhao, Yiwei, MD, PhD Liao, Haihui, MD, PhD Northstone, Kate, PhD Henderson, John, MD Alizadehfar, Reza, MD Ben-Shoshan, Moshe, MD Morgan, Kenneth, PhD Roberts, Graham, DM Masthoff, Laury J.N., MD Pasmans, Suzanne G.M.A., MD, PhD van den Akker, Peter C., MD Wijmenga, Cisca, PhD Hourihane, Jonathan O’B., PhD Palmer, Colin N.A., PhD Lack, Gideon, PhD Clarke, Ann, MD, MSc Hull, Peter R., MD, PhD Irvine, Alan D., MD McLean, W. H. Irwin, PhD, DSc
subjects:	AD, Atopic dermatitis Allergens Allergies Allergy Allergy and Immunology ALSPAC, Avon Longitudinal Study of Parents and Children Arachis hypogaea ASTHMA ATOPIC-DERMATITIS Avon Longitudinal Study of Parents beverages Canada Case-Control Studies CHILDHOOD CHILDREN Children & youth Dermatitis ECZEMA Etiology Europe Filaggrin Filaggrin Proteins FLG, Filaggrin food Food allergies Food allergy FOOD CHALLENGES Food hypersensitivity Genetic Association Studies Genetic engineering Genetic Predisposition to Disease Genetic research Genetic Variation Health aspects Heritability Humans Hypersensitivity Hypersensitivity, Immediate IgE Immunoglobulin E Immunology Intermediate Filament Proteins - genetics Ireland MANAGEMENT Medical colleges Mutation Netherlands Nuts Odds ratio OR, Odds ratio Peanut allergy Peanut Hypersensitivity - genetics Peanuts PREVALENCE PRICK Replication Respiratory agents risk factor Risk Factors SKIN BARRIER FUNCTION Skin prick test Skin tests Special section SPT, Skin prick test UK, United Kingdom UMCG Approved United Kingdom
ispartof:	Journal of allergy and clinical immunology, 2011, Vol.127 (3), p.661-667
description:	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.
language:	eng
source:	Alma/SFX Local Collection
identifier:	ISSN: 0091-6749
fulltext:	fulltext
issn:	0091-6749 1097-6825
url:	Link

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

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Brown, Sara J., MD ; Asai, Yuka, MD ; Cordell, Heather J., DPhil ; Campbell, Linda E., MSc ; Zhao, Yiwei, MD, PhD ; Liao, Haihui, MD, PhD ; Northstone, Kate, PhD ; Henderson, John, MD ; Alizadehfar, Reza, MD ; Ben-Shoshan, Moshe, MD ; Morgan, Kenneth, PhD ; Roberts, Graham, DM ; Masthoff, Laury J.N., MD ; Pasmans, Suzanne G.M.A., MD, PhD ; van den Akker, Peter C., MD ; Wijmenga, Cisca, PhD ; Hourihane, Jonathan O’B., PhD ; Palmer, Colin N.A., PhD ; Lack, Gideon, PhD ; Clarke, Ann, MD, MSc ; Hull, Peter R., MD, PhD ; Irvine, Alan D., MD ; McLean, W. H. Irwin, PhD, DSc

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1	EISSN: 1097-6825
2	DOI: 10.1016/j.jaci.2011.01.031
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United States: Elsevier Inc

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AD, Atopic dermatitis ; Allergens ; Allergies ; Allergy ; Allergy and Immunology ; ALSPAC, Avon Longitudinal Study of Parents and Children ; Arachis hypogaea ; ASTHMA ; ATOPIC-DERMATITIS ; Avon Longitudinal Study of Parents ; beverages ; Canada ; Case-Control Studies ; CHILDHOOD ; CHILDREN ; Children & youth ; Dermatitis ; ECZEMA ; Etiology ; Europe ; Filaggrin ; Filaggrin Proteins ; FLG, Filaggrin ; food ; Food allergies ; Food allergy ; FOOD CHALLENGES ; Food hypersensitivity ; Genetic Association Studies ; Genetic engineering ; Genetic Predisposition to Disease ; Genetic research ; Genetic Variation ; Health aspects ; Heritability ; Humans ; Hypersensitivity ; Hypersensitivity, Immediate ; IgE ; Immunoglobulin E ; Immunology ; Intermediate Filament Proteins - genetics ; Ireland ; MANAGEMENT ; Medical colleges ; Mutation ; Netherlands ; Nuts ; Odds ratio ; OR, Odds ratio ; Peanut allergy ; Peanut Hypersensitivity - genetics ; Peanuts ; PREVALENCE ; PRICK ; Replication ; Respiratory agents ; risk factor ; Risk Factors ; SKIN BARRIER FUNCTION ; Skin prick test ; Skin tests ; Special section ; SPT, Skin prick test ; UK, United Kingdom ; UMCG Approved ; United Kingdom

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Journal of allergy and clinical immunology, 2011, Vol.127 (3), p.661-667

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1	2011 American Academy of Allergy, Asthma & Immunology
2	info:eu-repo/semantics/restrictedAccess
3	Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
4	COPYRIGHT 2011 Elsevier B.V.
5	Copyright Elsevier Limited Mar 2011
6	2011 Mosby, Inc. 2011 American Academy of Allergy, Asthma & Immunology

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19	Clarke, Ann, MD, MSc
20	Hull, Peter R., MD, PhD
21	Irvine, Alan D., MD
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9	Ben-Shoshan, Moshe, MD
10	Morgan, Kenneth, PhD
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13	Pasmans, Suzanne G.M.A., MD, PhD
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17	Palmer, Colin N.A., PhD
18	Lack, Gideon, PhD
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creationdate	2011
title	Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy
author	Brown, Sara J., MD ; Asai, Yuka, MD ; Cordell, Heather J., DPhil ; Campbell, Linda E., MSc ; Zhao, Yiwei, MD, PhD ; Liao, Haihui, MD, PhD ; Northstone, Kate, PhD ; Henderson, John, MD ; Alizadehfar, Reza, MD ; Ben-Shoshan, Moshe, MD ; Morgan, Kenneth, PhD ; Roberts, Graham, DM ; Masthoff, Laury J.N., MD ; Pasmans, Suzanne G.M.A., MD, PhD ; van den Akker, Peter C., MD ; Wijmenga, Cisca, PhD ; Hourihane, Jonathan O’B., PhD ; Palmer, Colin N.A., PhD ; Lack, Gideon, PhD ; Clarke, Ann, MD, MSc ; Hull, Peter R., MD, PhD ; Irvine, Alan D., MD ; McLean, W. H. Irwin, PhD, DSc

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0	AD, Atopic dermatitis
1	Allergens
2	Allergies
3	Allergy
4	Allergy and Immunology
5	ALSPAC, Avon Longitudinal Study of Parents and Children
6	Arachis hypogaea
7	ASTHMA
8	ATOPIC-DERMATITIS
9	Avon Longitudinal Study of Parents
10	beverages
11	Canada
12	Case-Control Studies
13	CHILDHOOD
14	CHILDREN
15	Children & youth
16	Dermatitis
17	ECZEMA
18	Etiology
19	Europe
20	Filaggrin
21	Filaggrin Proteins
22	FLG, Filaggrin
23	food
24	Food allergies
25	Food allergy
26	FOOD CHALLENGES
27	Food hypersensitivity
28	Genetic Association Studies
29	Genetic engineering
30	Genetic Predisposition to Disease
31	Genetic research
32	Genetic Variation
33	Health aspects
34	Heritability
35	Humans
36	Hypersensitivity
37	Hypersensitivity, Immediate
38	IgE
39	Immunoglobulin E
40	Immunology
41	Intermediate Filament Proteins - genetics
42	Ireland
43	MANAGEMENT
44	Medical colleges
45	Mutation
46	Netherlands
47	Nuts
48	Odds ratio
49	OR, Odds ratio
50	Peanut allergy
51	Peanut Hypersensitivity - genetics
52	Peanuts
53	PREVALENCE
54	PRICK
55	Replication
56	Respiratory agents
57	risk factor
58	Risk Factors
59	SKIN BARRIER FUNCTION
60	Skin prick test
61	Skin tests
62	Special section
63	SPT, Skin prick test
64	UK, United Kingdom
65	UMCG Approved
66	United Kingdom

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1	Asai, Yuka, MD
2	Cordell, Heather J., DPhil
3	Campbell, Linda E., MSc
4	Zhao, Yiwei, MD, PhD
5	Liao, Haihui, MD, PhD
6	Northstone, Kate, PhD
7	Henderson, John, MD
8	Alizadehfar, Reza, MD
9	Ben-Shoshan, Moshe, MD
10	Morgan, Kenneth, PhD
11	Roberts, Graham, DM
12	Masthoff, Laury J.N., MD
13	Pasmans, Suzanne G.M.A., MD, PhD
14	van den Akker, Peter C., MD
15	Wijmenga, Cisca, PhD
16	Hourihane, Jonathan O’B., PhD
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0	Brown, Sara J., MD
1	Asai, Yuka, MD
2	Cordell, Heather J., DPhil
3	Campbell, Linda E., MSc
4	Zhao, Yiwei, MD, PhD
5	Liao, Haihui, MD, PhD
6	Northstone, Kate, PhD
7	Henderson, John, MD
8	Alizadehfar, Reza, MD
9	Ben-Shoshan, Moshe, MD
10	Morgan, Kenneth, PhD
11	Roberts, Graham, DM
12	Masthoff, Laury J.N., MD
13	Pasmans, Suzanne G.M.A., MD, PhD
14	van den Akker, Peter C., MD
15	Wijmenga, Cisca, PhD
16	Hourihane, Jonathan O’B., PhD
17	Palmer, Colin N.A., PhD
18	Lack, Gideon, PhD
19	Clarke, Ann, MD, MSc
20	Hull, Peter R., MD, PhD
21	Irvine, Alan D., MD
22	McLean, W. H. Irwin, PhD, DSc

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atitle

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

jtitle

Journal of allergy and clinical immunology

addtitle

J Allergy Clin Immunol

date

2011

risdate

2011

volume

127

issue

spage

661

epage

667

pages

661-667

issn

0091-6749

eissn

1097-6825

notes

These authors contributed equally to this work.

abstract

cop

United States

pub

Elsevier Inc

pmid

21377035

doi

10.1016/j.jaci.2011.01.031

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