CARD14 gene mutations linked to psoriasis
MedWire News: Mutations in the caspase recruitment domain 14 gene (CARD14) are associated with plaque and pustular psoriasis and psoriatic arthritis, show findings from two studies published in the American Journal of Human Genetics.
"We have searched for almost two decades to find a single gene linked to plaque psoriasis," said senior author of both papers Anne Bowcock (Washington University School of Medicine, St Louis, USA) in a press statement.
"Individually, the rare mutations we have found likely confer a high risk for the disease, and we think they will be important in the search to find new, more effective treatments," she said.
Over 20 susceptibility loci for psoriasis have been discovered, the most significant of which is in psoriasis susceptibility locus 1 (PSORS1).
CARD14 protein increases nuclear factor-kappa B (NF-kB) activation, which in turn stimulates signaling molecules that attract inflammatory cells to the skin, as seen in psoriasis, making it a good candidate gene for the condition.
In one of the studies, 20 variants in CARD14, some of which were only seen in a few individuals, were genotyped to determine association with plaque psoriasis in over 6000 patients with the condition and 4000 controls.
The most significant association was with the single nucleotide polymorphism rs11652075 (c.2458C>T), which also showed linkage with PSORS1.
In the other paper, the investigators describe two gain of function mutations in CARD14, c.349G>A and c.349+5G>A, which altered splicing in exons 3 and 4 of the gene. These alterations resulted in enhanced NF-kB activation and upregulation of various psoriasis-associated genes in the skin cells of carriers. The c.349G>A polymorphism was also linked to psoriatic arthritis.
Of note, the team also found a de novo mutation, c.413A>C, in a child with pustular psoriasis.
"This is significant because it tells us that CARD14 mutations alone are enough to lead to psoriasis, possibly after an early trigger such as an infection," Bowcock explained.
"You don't need anything else. This really highlights the importance of finding rare mutations for common diseases like psoriasis."
The researchers say: "These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease."
By Helen Albert