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Researchers ID Psoriasis Predisposition Gene

NEW YORK (GenomeWeb News) – Mutations in the NF-kappaB activator-coding gene CARD14 have been linked to the most common form of psoriasis and appear to contribute to other manifestations of the disease as well, according to a Washington University-led team. The researchers described their findings in a pair of studies online yesterday in the American Journal of Human Genetics.

"Individually, the rare mutations we have found likely confer a high risk for the disease," Washington University genetics researcher Anne Bowcock, senior author of both new AJHG studies, said in a statement, "and we think they will be important in the search to find new, more effective treatments

In the first of the studies, she and her colleagues used exome and targeted sequencing to look more carefully at a chromosome 17 locus that had been implicated in psoriasis through a past linkage study. In the process, they tracked down rare mutations in CARD14 that appear to interact with triggers such as infection, injury, or other environmental exposures to cause plaque psoriasis, a form of the disease typified by scaly raised skin patches.

Along with its newly identified role in this prevalent form of the disease, results of the studies suggest CARD14 is involved in related conditions as well, the group found. For example, around one-third of the individuals from the European family tested to find the first rare, psoriasis-associated CARD14 mutations also suffered from psoriasis-related arthritis.

Another rare mutation in CARD14 was detected in a young Haitian girl with pustular psoriasis but no family history of the disease. According to WashU's Bowcock, that finding hints that "CARD14 mutations alone are enough to lead to psoriasis, possibly after an early trigger such as an infection."

"This really highlights the importance of finding rare mutations for common diseases like psoriasis," she said in a statement.

Bowcock and her co-authors used Roche-Nimblegen and Agilent kits, combined with Illumina GAIIx sequencing, to capture and sequence either whole exomes or targeted sequences from individuals belonging to the same psoriasis-affected European family in which the chromosome 17 locus was originally detected.

Exome sequencing for four individuals with psoriasis from this family — combined with targeted sequencing of the chromosome 17 region in another 14 affected and eight unaffected individuals from the family — uncovered suspicious mutations in CARD14 and in another nearby gene, SLC26A11.

By sequencing both genes in a Taiwanese family affected by psoriasis, the researchers were able to determine that it was rare mutations in CARD14 that corresponded with psoriasis in both the European and Taiwanese families.

Another mutation, this one de novo, was identified in a three-year old girl from Haiti who had developed pustular psoriasis as an infant.

Through their subsequent skin cell line and gene expression experiments, the team also garnered clues to some of the functional consequences of CARD14 alterations, showing that some of these mutations bump up activity of downstream signaling pathways.

In a second AJHG study, the researchers focused on other rare and common variants in CARD14, looking at the frequency of these alterations and their potential ties to psoriasis-related conditions.

When they looked at 15 rare, missense mutations in more than 6,000 individuals with psoriasis and around 4,000 unaffected control individuals, for instance, the researchers found that rare mutations in the gene tended to turn up more frequently in individuals with psoriasis than those without.

"[O]ur findings provide evidence of some rare CARD14 variants that predispose to psoriasis and, possibly, to psoriatic arthritis," researchers wrote, "and they suggest that common variants in this region might also predispose to disease."

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