Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.
Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Colin N A
CN
Palmer
Alan D
AD
Irvine
Ana
A
Terron-Kwiatkowski
Yiwei
Y
Zhao
Haihui
H
Liao
Simon P
SP
Lee
David R
DR
Goudie
Aileen
A
Sandilands
Linda E
LE
Campbell
Frances J D
FJ
Smith
Gráinne M
GM
O'Regan
Rosemarie M
RM
Watson
Jo E
JE
Cecil
Sherri J
SJ
Bale
John G
JG
Compton
John J
JJ
DiGiovanna
Philip
P
Fleckman
Sue
S
Lewis-Jones
Gehan
G
Arseculeratne
Ann
A
Sergeant
Colin S
CS
Munro
Brahim
B
El Houate
Ken
K
McElreavey
Liselotte B
LB
Halkjaer
Hans
H
Bisgaard
Somnath
S
Mukhopadhyay
W H Irwin
WH
McLean
D000483:Alleles; D001249:Asthma / Q000235:genetics / Q000276:immunology; D002648:Child; D015331:Cohort Studies; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008297:Male; D009154:Mutation; D010375:Pedigree; D012879:Skin Physiological Phenomena
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins