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

被引:334
作者
Brown, Sara J. [1 ,3 ,4 ]
Asai, Yuka [5 ,6 ]
Cordell, Heather J. [11 ]
Campbell, Linda E.
Zhao, Yiwei
Liao, Haihui
Northstone, Kate [12 ]
Henderson, John [12 ]
Alizadehfar, Reza [10 ]
Ben-Shoshan, Moshe [6 ,10 ]
Morgan, Kenneth [8 ,9 ]
Roberts, Graham [13 ,14 ]
Masthoff, Laury J. N. [15 ]
Pasmans, Suzanne G. M. A. [15 ]
van den Akker, Peter C. [16 ]
Wijmenga, Cisca [16 ]
Hourihane, Jonathan O'B. [17 ]
Palmer, Colin N. A. [2 ]
Lack, Gideon [18 ]
Clarke, Ann [6 ,7 ]
Hull, Peter R.
Irvine, Alan D. [4 ,19 ,20 ]
McLean, W. H. Irwin
机构
[1] Univ Dundee, Ninewells Hosp & Med Sch, Div Mol Med, Coll Life Sci,Inst Med Sci,Epithelial Genet Grp, Dundee DD1 5EH, Scotland
[2] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 5EH, Scotland
[3] Univ Dundee, Ninewells Hosp & Med Sch, Dept Dermatol, Dundee DD1 9SY, Scotland
[4] Trinity Coll Dublin, Coll Green, Dublin, Ireland
[5] McGill Univ, Ctr Hlth, Div Dermatol, Montreal, PQ, Canada
[6] McGill Univ, Ctr Hlth, Div Clin Epidemiol, Montreal, PQ, Canada
[7] McGill Univ, Ctr Hlth, Dept Med, Div Clin Immunol Allergy, Montreal, PQ, Canada
[8] McGill Univ, Dept Human Genet, Montreal, PQ, Canada
[9] McGill Univ, Res Inst, Ctr Hlth, Montreal, PQ, Canada
[10] McGill Univ, Dept Pediat, Div Clin Immunol Allergy, Ctr Hlth, Montreal, PQ H3A 2T5, Canada
[11] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England
[12] Univ Bristol, Dept Social Med, Bristol BS8 1TH, Avon, England
[13] Univ Southampton, Sch Med, Southampton SO9 5NH, Hants, England
[14] Univ Southampton, Resp Biomed Res Unit, Southampton SO9 5NH, Hants, England
[15] Univ Med Ctr Utrecht, Dept Pediat Dermatol Allergol, Wilhelminas Children Hosp, Utrecht, Netherlands
[16] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 AB Groningen, Netherlands
[17] Univ Coll Cork, Dept Paediat & Child Hlth, Cork, Ireland
[18] Kings Coll London, London, England
[19] Univ Saskatchewan, Div Dermatol, Saskatoon, SK S7N 0W0, Canada
[20] Our Ladys Childrens Hosp, Dublin, Ireland
基金
英国惠康基金; 英国医学研究理事会; 加拿大健康研究院;
关键词
Atopic dermatitis; filaggrin; IgE; peanut allergy; risk factor; SKIN BARRIER FUNCTION; ATOPIC-DERMATITIS; CHILDREN; FOOD; PRICK; PREVALENCE; MANAGEMENT; MUTATIONS; DIAGNOSIS; ASTHMA;
D O I
10.1016/j.jaci.2011.01.031
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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. (J Allergy Clin Immunol 2011;127:661-7.)
引用
收藏
页码:661 / 667
页数:7
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