The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study.
BACKGROUND
Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma.


OBJECTIVE
We sought to determine the natural history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study.


METHODS
We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991.


RESULTS
FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 x 10(-8)). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 x 10(-11)). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 x 10(-27)).


CONCLUSIONS
FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the "eczema plus early wheeze" and "eczema plus asthma" phenotypes.
Henderson
John
J
Department of Community-based Medicine, University of Bristol, Bristol, United Kingdom.
Northstone
Kate
K
Lee
Simon P
SP
Liao
Haihui
H
Zhao
Yiwei
Y
Pembrey
Marcus
M
Mukhopadhyay
Somnath
S
Smith
George Davey
GD
Palmer
Colin N A
CN
McLean
W H Irwin
WH
Irvine
Alan D
AD
D000483:Alleles; D001249:Asthma / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003876:Dermatitis, Atopic / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D004485:Eczema / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D007223:Infant; D007381:Intermediate Filament Proteins / Q000172:deficiency / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D012135:Respiratory Sounds / Q000175:diagnosis / Q000235:genetics / Q000276:immunology
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins