Andrew Blauvelt, MD, MBA
Immunodermatology is an important content area for dermatologists to consider when managing patients with psoriasis. The genetics of psoriasis has been an exciting and complex area of research over the last few years, especially in terms of how genetics relate to the immunology of psoriasis. A recent paper highlighted how psoriasis genetics and pathogenesis are much more complicated than was formerly believed. Previously, there were 26 identified genetic susceptibility loci associated with psoriasis risk, and now there have been an additional 15 loci identified. Dr. Blauvelt, when discussing psoriasis with his patients, describes it as a complex polygenic disease; yet, according to Dr. Blauvelt, up to 60% of psoriasis patients will have no other family members with the disease. According to the paper, investigators are “just scratching the surface” and these 41 genetic signals account for approximately 22 percent of estimated psoriasis heritability and further genetic studies, including fine-mapping studies and searches for uncommon susceptibility variants, are in order (Tsoi LC, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44(12):1341-1348).
It is also important to consider the overlap between psoriasis genes and susceptibility genes identified for other autoimmune diseases, such as Crohn’s disease, ulcerative colitis, celiac disease, ankylosing spondylitis, rheumatoid arthritis, systemic lupus, multiple sclerosis, and types 1 and 2 diabetes. All of these diseases are polygenic (numerous genes are contributing to the susceptibility), which is a common theme of many common diseases. Of particular interest is the fact that 11 out of 41 susceptibility genes overlap between psoriasis and Crohn’s disease; in fact, six of the 11 genes are related to the IL-23/Th17 cell signaling pathway, suggesting that Crohn’s disease may respond to IL-23/Th17 blockade.
Psoriasis genes fall into five major functional categories and are either related to the innate or acquired immune system. These categories include genes linked with IL-23/Th17 cell activation (acquired); antigen presentation (acquired); type 1 interferon induction (innate); NF-kB signaling (innate); and skin barrier function (innate). Genes that are psoriasis-specific, i.e., no other disease associations, are mostly associated with innate immunity.
The genetic basis for generalized pustular psoriasis has been identified. Mutations occur in the gene that encodes for the IL-36 receptor antagonist. This is an example of classic Mendelian inheritance, in that patients who have mutations in this gene develop disease; if they do not have defects, then they do not have the disease. Therapeutically, there is no IL-36 antagonist drug yet, however, this may be developed in the future for patients with generalized pustular psoriasis. IL-36 normally stimulates keratinocytes to produce IL- 8, which is a major neutrophil chemotactic factor. IL-36 will drive neutrophils into the skin, and patients who have this defect in their IL-36 antagonist will have uncontrolled levels of IL-36, leading to elevations in other more downstream pro-inflammatory cytokines (TNF, IL-8, IL-6, IL-1).
CARD14 is another example of Mendelian inheritance, being that patients who have critical mutations in this gene develop chronic plaque psoriasis. On chromosome 17, a mutation in Card14 (G to A) at position 349 was seen in certain familial cases of psoriasis. CARD14 mutation is involved in the innate immune system. Dysfunction in this gene leads to increased NF-kB activity; this, in turn, leads to increased pro-inflammatory cytokine production by keratinocytes.
Numerous other CARD14 variations are associated with non-familial cases of psoriasis as well. These variations however, are not Mendelian. The genetic variations translate into increased NF-kB activity in keratinocytes and increased risk to develop psoriasis.
Dr. Blauvelt notes that this gene is very clinically relevant as it relates to the mechanism of action of ustekinumab. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. If patients don’t have fully functional IL-23 receptor, then IL-23 does not function well as a stimulator of Th17 cells; thus, this gene defect protects against psoriasis development. This is a genetic “hit” to the system, whereas ustekinumab would be a pharmacologic “hit” to the system.
Other genes associated with the IL-23/Th17 pathway include the p19 subunit and the p40 subunit of IL-23 itself.
There is a tremendous amount of new information regarding genes and psoriasis. Psoriasis pathogenesis represents a complex interplay between innate (how the skin initially reacts) and acquired immunity (mostly related to the IL-23/Th17 pathway). There is certainly a lot more detailed research to come in this area. Regarding translating this information to the bedside, the hope is that genetic profiling will help clinicians predict severity and course of disease as well as to help determine the response to specific therapeutic agents.