Atopic Dermatitis Knowledge Centre
Pathophysiology
Genetic factors
Atopic dermatitis has strong familial associations, and the risk of developing the disease is nearly doubled in children with affected parents. Twin studies have shown that if one monozygotic twin has atopic dermatitis, the chance of the other twin having the condition is approximately 86%, compared with 21% between dizygotic twins.30 These findings demonstrate that the inheritance of specific susceptibility genes can predispose individuals towards developing atopic dermatitis. Genetic predisposition to a disease occurs when a specific genetic variation leads to altered biological responses resulting in either susceptibility to the condition or changes in how the body responds to the condition. In the case of atopic dermatitis, candidate genes have been located on a number of chromosomes.25, 30, 31 A list of these genes, and their associated clinical phenotype, is presented in the table below. As research into the underlying genetic susceptibility continues, this list is likely to increase.
| Gene | Gene product | Associated phenotype |
|---|---|---|
| FLG | profilaggrin | Extrinsic atopic dermatitis, early onset of atopic dermatitis |
| SPINK5 | LETKI | atopic dermatitis |
| TLR 2 | Toll-like receptor-2 | Severe atopic dermatitis with elevated IgE |
| TLR 9 | Toll-like receptor-9 | Intrinsic atopic dermatitis |
| IRF 2 | IFN regulatory factor 2 | atopic dermatitis (found in Japanese children) |
| GM-CSF | GM-CSF | Prevention of severe symptoms in atopic dermatitis patients |
| MS4A 2 | FCεR1β | atopic dermatitis |
| TGFβ1 | Transforming Growth Factor β | atopic dermatitis in children |
| IL3 | IL-3 | |
| IL4 | IL-4 | atopic dermatitis |
| IL12 | IL12 | Susceptibility to atopic dermatitis |
| IL13 | IL13 | atopic dermatitis with elevated total serum IgE |
| IL 18 | IL18 | atopic dermatitis |
| ILRA | IL-4 receptor α chain | Adult atopic dermatitis |
| STAT6 | Signal transducer and activator of transcription 6 |
Elevated serum IgE |
| PFH11 | Plant homology domain finger protein 11 | Childhood atopic dermatitis with elevated total serum IgE |
In addition to the direct effects of susceptibility genes, interactions between the genetic traits and the surrounding environment can increase the chances of developing atopic dermatitis and exacerbate the severity of the symptoms. For example, children with loss-of-function mutations in the FLG gene were statistically more likely to develop atopic dermatitis when exposed to cats from birth. Loss-of-functionFLG mutations alone are sufficient to predispose infants to atopic dermatitis32; however, the risk of developing the disease increases significantly when combined with exposure to cat allergens.33
References:
30. Bowcock AM, Cookson WO. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum Mol Genet 2004; 13 Spec No 1: R43-55.
25. Maintz L, Novak N. Getting more and more complex: the pathophysiology of atopic eczema. Eur J Dermatol 2007; 17: 267-83.
31. Ekelund E, Saaf A, Tengvall-Linder M, et al. Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis. Am J Hum Genet 2006; 78: 1060-5.
32. Sandilands A, O'Regan GM, Liao H, et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol 2006; 126: 1770-5.
33. Bisgaard H, Simpson A, Palmer CN, et al. Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 2008; 5: e131.
© February 2010 Astellas Pharma Europe LTD.
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