SMAD3 as an atopic dermatitis susceptibility gene in the Japanese population

Atopic dermatitis (AD) is a hereditary, pruritic, inflammatory, and chronic skin disease that occurs most commonly in early childhood but can persist in or even begin in adulthood. AD is a common disease of complex inheritance, and twin and family studies have confirmed the existence of a genetic predisposition to the development of AD, with a heritability of 0.72 [ ], although a clear Mendelian pattern of inheritance has not been established. Recent studies have emphasized the importance of skin barrier function in the development of AD. Loss-of-function mutations of the filaggrin gene (FLG) were found to be associated with AD in various ethnic populations [ ]. In addition to FLG, other factors such as epidermal growth factor, transforming growth factor (TGF)-β, and fibroblast growth factor are involved in the skin barrier function and repair [ ]. TGF-β plays a major role in regulating a variety of types of physiological and pathological inflammation and fibrosis. The principal transducers of signals upon TGF-β stimulation are mothers against decapentaplegic homologs 2 and 3 of Drosophila (SMAD2 and SMAD3). Using Smad3-knockout mice, it was reported that Smad3-null mice are resistant to radiation-induced skin fibrosis and inflammation [ ] and that dermal thickening was significantly reduced in Smad3-knockout mice upon ovalbumin sensitization compared with that in wild type mice [ ]. Dermal fibrosis and dermal thickening are important features of chronic AD lesions. SMAD3 is located on chromosome 15q, where suggestive evidence for the linkage of AD was found [ ]. In the present study, we investigated the possible association between the polymorphisms in SMAD3 and AD in the Japanese population. Detailed methods are provided as supplementary materials.