Published Online: April 11, 2013
Atopic dermatitis (AD) typically presents in early infancy and can take a variable clinical course. In the majority of children, AD resolves spontaneously by school age. It may, however, also take a relapsing course and persist until adulthood. Little is known about the genetic determinants of AD persistence.
In a recent article in The Journal of Allergy & Clinical Immunology (JACI), Esparza-Gordillo et al hypothesized that genetic factors influencing human inflammatory traits are likely to play a role in AD. Thus, taking advantage of previous genome-wide association studies they selected a set of candidate genetic variants influencing immune-related traits such as autoimmune disorders or chronic inflammatory bowel disease, and tested them for association with AD in over 16,000 study participants. Novel risk variants were then investigated in two independent birth cohorts to define their role in the prognosis/persistence of AD.
The authors identified a genetic variant causing an amino acid exchange in the Interleukin-6 receptor (IL6R), as a novel risk factor for persistent atopic dermatitis. The risk variant shifts the balance between the membrane-bound IL6R and the soluble IL6R signalling pathways favoring increased shedding of the soluble IL6R into body fluids. They demonstrate that AD patients have elevated plasma levels of soluble IL6R underlining the role of increased IL6R shedding in AD. These results point to targeted blockage of the soluble IL6R pathway as a novel therapeutic approach for persistent atopic dermatitis, especially in individuals carrying this common variant. Interestingly, global IL6R blockade with Tocilizumab is already approved for the treatment of rheumatoid arthritis. However, molecules specifically targeting the soluble IL6R are being developed and may have clinical efficacy in persistent atopic dermatitis with reduced side effects, such as bacterial infections, arising from simultaneous blockade of classical membrane-bound IL6R signalling.
The finding of a functional genetic variant influencing disease prognosis and specifically predisposing to persistent AD highlights the potential clinical implications of genetic studies. Additionally, this work suggests that available knowledge on the genetic determinants of inflammatory traits can be exploited for the identification of genetic risk factors underlying related diseases.
The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.