A literature review by researchers at National Jewish Health in Denver shows that two major biologic pathways are responsible for driving the development of atopic dermatitis. One is genetic, the other epigenetic, but both can lead to changes in gene expressions that impairs the immune system and skin barrier.
Although it is, in part, a heritable disease, the prevalence of atopic dermatitis has risen in recent years due to environmental factors. The surge in new cases has led to more interest in epigenetics research which explains how lifestyle and air pollution can alter gene expressions leading to atopic dermatitis.
The last comprehensive review — published in 2009 — analyzed five linkage studies and 111 targeted gene association studies. In June 2009, the availability and appreciation of epigenetic data had just started to grow. Over the next several years, an explosion in technologies — including next-generation methods such as exome analysis and high-throughput genetic expression profiling — spurred the publication of more than 30 new studies between January 2015 and June 2016 alone.3
Earlier studies that focused on individual candidate genes helped establish a focus on mutations in the filaggrin gene (FLG) as the pre-eminent atopic dermatitis risk factor, write Lianghua Bin, M.D., Ph.D., and Donald Y. M. Leung, M.D., Ph.D., of the National Jewish Health in Denver.
The present review, published in a 2016 issue of the journal Allergy, Asthma and Clinical Immunology, corroborates the 2009 Barnes review focus on skin barrier genes and immune response genes. It includes genetics and epigenetics studies on atopic dermatitis that were published between 2009 and 2016.
A PubMed search yielded 19 candidate gene association studies (65 genes; with more than half having at least one positive association) and 13 genome-wide association studies (GWAS) in atopic dermatitis. Along with identifying additional associations and risk loci, Bin and Leung highlight how advances in genetic research have begun to illuminate the roles these defects play in the development of atopic dermatitis.
Among skin barrier genes, FLG is the most significant risk factor for atopic dermatitis pathogenesis, and two of its known mutations — R501X and 2282del4 — have shown the strongest association for atopic dermatitis in Caucasians (18% and 48% of moderate to severe AD, respectively).4
Among environmental factors, recent research shows that phthalate metabolite levels are significantly associated with increased atopic dermatitis risk, and that children with FLG P478S mutations experience increased skin absorption of phthalate. Maternal FMG mutations, independent of mutation inheritance, also can act as strong environmental risk factors, the authors say.
Additional research implicates genes that impair formation of tight junctions within the epidermal granular layer. For example, owing to Th2 cytokines and genetic variants, expression of claudin-1/CLDN1 is reduced in AD-affected skin. Several studies also highlight the role of defects in the serine protease inhibitor of Kazal type 5 (SPINK5) gene, a crucial protease inhibitor for epidermal homeostasis.