Parsing psoriasis: Common DNA variations increase risk of developing skin condition

June 1, 2008

Seven newly identified sites of common DNA variations increase the risk for psoriasis and psoriatic arthritis. The whole genome association study of more than 300,000 single nucleotide polymorphisms (SNPs) was published in the March issue of PLoS Genetics. The goal was to identify new genes and new pathways for drug development.

Key Points

National report - Common DNA variations at seven newly identified sites increase the risk for psoriasis and psoriatic arthritis.

The whole genome association study of more than 300,000 single nucleotide polymorphisms (SNPs) was published in the March issue of PLoS Genetics. The goal was to identify new genes and new pathways for drug development.

The study first compared the genomes of 223 psoriasis patients, 91 of whom had psoriatic arthritis with a strong family history of psoriasis, with the SNPs of 519 health control subjects, looking for differences that could be linked to the diseases.

"The region with the strongest effect is the MHC that contains HLA-C. That is probably not surprising, but we weren't sure when we started out," says Anne Bowcock, Ph.D., who led the research team at Washington University in St. Louis School of Medicine, St. Louis.

Dr. Bowcock says researchers confirmed the importance of IL-12/23 genes associated with psoriasis, but also found "an interesting association between interleukin-2 and interleukin-21. This region is also implicated in five other autoimmune diseases: type 1 diabetes, Grave's disease, celiac disease, rheumatoid arthritis and systemic lupus erythematosus.

"It suggests that drugs that target IL-2 and IL-21 might be useful in treating psoriasis, psoriatic arthritis and a number of other autoimmune disorders," she says. "It may be that these variants are affecting the different genes regulating T cells."

Other sites of variation contained genes whose role in psoriasis is not yet understood - for example, granulysin, Dr. Bowcock tells Dermatology Times.

Next step

"Essentially, these studies become signposts for a variant, and you have to go and find the true variant," Dr. Bowcock says.

"We want to find them because we want to understand the underlying biology. We also want a full understanding of the genetic contribution to psoriasis and psoriatic arthritis and how they interact with environmental triggers, such as viral infection," she says.

Dr. Bowcock is making this the focus of her ongoing research. She also is participating in the GAIN (Genetic Association Information Network) study, in collaboration with the University of Michigan and the University of Utah, that seeks to identify the full genetic contribution to psoriasis.

'Messy' disease

Alexa Boer Kimball, M.D., M.P.H., vice chairman of the department of dermatology at Massachusetts General Hospital, Boston, calls psoriasis "a messy disease. There clearly are multiple factors that play a role, as well as compensatory pathways that can affect it."

Dr. Kimball sees basic research such as this study, in parallel with clinical studies such as those of IL-12/23 inhibitors, as "a wonderful example of bench-to-bedside translation," informing each other in an iterative process.

"We already know that some of these agents work, so this is providing more of an explanation of how they work," she says.

Given the complex nature of psoriasis, she says it is unlikely there will be a single silver bullet that will resolve all of the affliction in all patients.

"But if you look at the success of the IL-12/23 inhibitors that are out there, particularly the data from the phase 2 Abbott study, 90 percent to 93 percent of the patients have a PASI (Psoriasis Area and Severity Index) 75 response. Almost everybody essentially clears (their symptoms) with that therapy at those doses.

"Now, that was only plaque psoriasis, but that is the most common form out there. So it does suggest that some of these directed therapies may work in a tremendous number of patients, if you hit the right part of the pathway," Dr. Kimball says.

Disclosures: Dr. Bowcock's work was supported, in part, by grants from the National Institutes of Health. Dr. Kimball reports no relevant financial conflicts of interest.

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