Psoriasis researchers find new genes, new pathways
“They give us new genes, new genetic variants and new pathways that are associated with psoriasis.”—Anne Bowcock, PhD
Taken together, “they give us new genes, new genetic variants and new pathways that are associated with psoriasis,” said Anne Bowcock, PhD, professor of genetics at Washington University School of Medicine in St. Louis, who is an author on 2 of the 3 papers. This research “will definitely give us new drugs and ultimately, we will want to subtype patients based on their genetic profile,” she told MSKreport.com.Still, a great deal more work is needed before such personalized medicine impacts psoriasis care. “We need to know what is conferring risk as the genes we have identified so far only account for a small proportion.”
In one study,1 the researchers scanned nearly 450,000 single nucleotide polymorphisms (SNPs) in each of the genomes of 1,409 psoriasis patients and compared the DNA variations to those in 1,436 healthy controls. The initial scans highlighted differences in at least 3 previously identified DNA sites, with HLA-Cw6 producing the strongest signal. The investigators then tested the validity of 18 gene variants in another group of 5,048 psoriasis patients and 5,041 controls. This work produced a total of 7 confirmed variants that increase the risk of psoriasis, 4 of which were novel. Moreover, 5 of these variants cluster in 2 distinct pathways that involve IL-23 and NF-κB. Both of these pathways are targeted by biological therapies that are highly effective against psoriasis.
Psoriasis researchers begin to piece together the puzzle
Two regions identified by the study contain genes—TNFAIP3 and TNIP1—that bind to each other and work together to act as a “brake” on NF-κB signaling. Variants of TNFAIP3 also have been associated with rheumatoid arthritis and lupus. The 4th novel locus contains IL4 and IL13, genes that support the development of Th2 cells. This new research, together with recent immunology work by some of the same researchers, links IL12B, IL23A, IL23R and IL4/IL13 together in a common functional pathway.
“This study gives us a number of new genes and pathways that tell us more about the pathogenesis of psoriasis and suggest new targets for treatments namely TNFAIP3 and TNIP1,” Dr. Bowcock told MSKreport.com.
A second study2 of 2,831 psoriasis patients found that the absence of two skin genes—LCE3B and LCE3C—increases the risk of psoriasis. Both genes are part of the epidermal barrier and are normally activated after an injury to the skin. The researchers suspect the deletion of the genes could lead to an inappropriate immune response resulting from a barrier defect.
The third study3 also identified the susceptibility variant within the LCE gene cluster in 1q21, and confirmed 2 known susceptibility loci—one near HLA-C in the major histocompatibility complex (MHC) and the other IL12B, which encodes a component of IL-23.
Translating research into practice
“The studies so far have identified regions of the genome where there are associations and we measure how frequently these markers occur in [psoriasis] cases versus controls,” explained James Elder, MD, PhD, a professor in the department of dermatology at the University of Michigan in Ann Arbor, and an author on 2 of the 3 studies. “When they are higher in cases then controls, we know there has to be something going on there [but] in most cases, we still don’t exactly know what is wrong or different in these genes in people who have psoriasis.”
These are complex problems biologically, he said. “We still don’t know why HLA-Cw6 causes problems. We have ideas, but we don’t have facts.” This gene was previously implicated in psoriasis by Dr. Elder in 2006.
“We really have quite a long way to go,” he said. Dr. Elder and his colleagues are now typing DNA from 3,000 cases and 3,000 controls for about 10,000 markers—4,000 to identify the causal variants and another 6,000 to see if any of the less significant signals from the initial scan can be replicated.
“We expect to identify several more associated gene regions in this follow-up study, and eventually as many as fifty,” he said. “But at the end of the day, thousands of genes contribute to the risk of developing psoriasis, but they each do so in a very small way—so small that we may not be able to detect many of them.”
But that doesn’t mean that there won’t be new drugs. New targets being investigated by pharma include the Il23A gene and other interleukins in an “epidermal defense pathway” known to be turned on by IL-23, as well as TNFAIP3 and TNIP1, he said.
“Better drugs are on the way,” he said. The new findings may also affect how—and when—psoriasis is diagnosed. “By the time we have a catalog of 30 to 40 genetic variants, it may be possible to get a pretty good idea of what somebody's risk for psoriasis is,” he said.
References
1. Nair RP, Duffin KC, Helms C, et al. Genome-wide scan reveal association of psoriasis with IL-23. Nature Genetics. 2009; doi:10.1038ng.311 [published online ahead of print January 25, 2009].
2. De Cid R, Riveira-Muniz E, Zeeuwen PLJM, et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nature Genetics. 2009; doi:10.1038ng.313 [published online ahead of print January 25, 2009].
3. Zhang X-J, Huang W, Sun L-D, et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nature Genetics. 2009; doi:10.1038ng.310 [published online ahead of print January 25, 2009].
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