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


CONCLUSIONS
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.
Gao
Pei-Song
PS
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, Md 21224, USA.
Rafaels
Nicholas M
NM
Hand
Tracey
T
Murray
Tanda
T
Boguniewicz
Mark
M
Hata
Tissa
T
Schneider
Lynda
L
Hanifin
Jon M
JM
Gallo
Richard L
RL
Gao
Li
L
Beaty
Terri H
TH
Beck
Lisa A
LA
Barnes
Kathleen C
KC
Leung
Donald Y M
DY
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007617:Kaposi Varicelliform Eruption / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology; D055815:Young Adult
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins