Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum

被引:174
作者
Gao, Pei-Song [1 ]
Rafaels, Nicholas M. [1 ]
Hand, Tracey [1 ]
Murray, Tanda [2 ]
Boguniewicz, Mark [3 ]
Hata, Tissa [4 ]
Schneider, Lynda [5 ]
Hanifin, Jon M. [6 ]
Gallo, Richard L. [4 ]
Gao, Li [1 ]
Beaty, Terri H. [2 ]
Beck, Lisa A. [7 ]
Barnes, Kathleen C. [1 ]
Leung, Donald Y. M. [3 ]
机构
[1] Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD 21224 USA
[2] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA
[3] Natl Jewish Hlth, Dept Pediat, Denver, CO USA
[4] Univ Calif San Diego, Div Dermatol, San Diego, CA 92103 USA
[5] Childrens Hosp, Div Immunol, Boston, MA 02115 USA
[6] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97201 USA
[7] Univ Rochester, Med Ctr, Dept Dermatol, Rochester, NY 14642 USA
基金
美国国家卫生研究院;
关键词
Atopic dermatitis; eczema herpeticum; filaggrin; R501X; 2282del4; single nucleotide polymorphisms; OF-FUNCTION VARIANTS; ICHTHYOSIS VULGARIS; NULL MUTATIONS; GENE; SUSCEPTIBILITY; ASTHMA; POLYMORPHISMS; PREVALENT; SEVERITY; CHILDREN;
D O I
10.1016/j.jaci.2009.07.034
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis ( AD). Associations have not been reported in African ancestry populations. Atopic dermatitis eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous herpes simplex virus infections. Objective: We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. Methods: Two common loss-of-function mutations plus 9 FLG single nucleotide polymorphisms were genotyped in 278 European American patients with AD, of whom 112 had ADEH, and 157 nonatopic controls. Replication was performed on 339 African American subjects. Results: Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects (P = 1.46 x 10(-5), 3.87 x 10(-5), respectively), but the frequency of the R501X mutation was 3 times higher (25% vs 9%) for ADEH than for AD without eczema herpeticum (EH) (odds ratio [OR], 3.4; 1.7-6.8; P = .0002). Associations with ADEH were stronger with the combined null mutations (OR, 10.1; 4.7-22.1; P = 1.99 x 10(-11)). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African American subjects, but present among patients with AD (3.2%; P = .035) and common among patients with ADEH (9.4%; P = .0049). However, the 2282del4 mutation was absent among African American patients with ADEH and rare (<1%) among healthy individuals. Conclusion: The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition. (J Allergy Clin Immunol 2009;124:507-13.)
引用
收藏
页码:507 / U178
页数:14
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