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.
Palmer
Colin N A
CN
Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Irvine
Alan D
AD
Terron-Kwiatkowski
Ana
A
Zhao
Yiwei
Y
Liao
Haihui
H
Lee
Simon P
SP
Goudie
David R
DR
Sandilands
Aileen
A
Campbell
Linda E
LE
Smith
Frances J D
FJ
O'Regan
Gráinne M
GM
Watson
Rosemarie M
RM
Cecil
Jo E
JE
Bale
Sherri J
SJ
Compton
John G
JG
DiGiovanna
John J
JJ
Fleckman
Philip
P
Lewis-Jones
Sue
S
Arseculeratne
Gehan
G
Sergeant
Ann
A
Munro
Colin S
CS
El Houate
Brahim
B
McElreavey
Ken
K
Halkjaer
Liselotte B
LB
Bisgaard
Hans
H
Mukhopadhyay
Somnath
S
McLean
W H Irwin
WH
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