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Polygenic Theory


Ann Arbor, Mich. - Although researchers agree that the strongest psoriasis susceptibility locus is in the major histocompatibility complex (MHC), only about 10 percent of psoriasis patients that carry the known MHC gene also get psoriasis. While environmental factors may in part account for the puzzling fact, researchers agree that the psoriasis gene at the MHC locus is not the whole story.

Other loci located not on chromosome 6, like the MHC locus, but on chromosomes 1, 3, 4, 10, 16, 17, 19, and 20, may also be associated with psoriasis, according to James T. Elder, M.D., Ph.D., and co-workers (Arch Dermatol. 2001;137:1447-1454). Several of these loci have been given names to designate their apparent association with psoriasis. "PSORS1 is the locus on the MHC chromosome," Dr. Elder said. "PSORS2 is on chromosome 17, PSORS3 is on chromosome 4, PSORS4 is on chromosome 1, and so on up to PSORS8. In addition to PSORS1, only PSORS2 has been independently confirmed by multiple groups."

"The fact that three research groups have detected PSORS2 on chromosome 17 lends credence that this locus contains a bona fide psoriasis gene," added Dr. Elder, associate professor, department of dermatology, University of Michigan Medical Center, Ann Arbor.

"Because we can point to at least two genes that we are confident must really predispose to psoriasis, the work accomplished so far provides evidence for the polygenic hypothesis. This hypothesis states that more than one disease gene is necessary to produce disease in any given individual. This hypothesis can explain why only 10 percent of PSORS1 carriers get psoriasis: they have not received the susceptibility genes that reside on other chromosomes," Dr. Elder said.

As for the remaining loci, PSORS4 and PSORS5 have been reported by two groups, and PSORS3, PSORS6, PSORS7, and PSORS8 have each been reported by one group. According to Dr. Elder, "it's still anybody's guess which of these additional loci will prove to be real."

The beauty of genetics, Dr. Elder said, is that inheritance operates only by Mendel's rules. In other words, one does not have to know the function of a particular gene in order to implicate it in a disease process such as psoriasis.

The locus on chromosome 3 (PSORS5) has been tracked all the way to the level of the gene, according to Dr. Elder (Hewett et al. Genomics. 2002;79:305-314).

Although many non-MHC loci have been reported, research still focuses on identifying the MHC gene on chromosome 6. Dr. Elder cited a recent report (Asumalahti K et al. Hum Mol Genet. 2002;11:589-597) claiming that a gene called HCR on this chromosome has a causal effect in psoriasis. Dr. Elder and co-workers, however, have reported that the association of the HCR gene with psoriasis is the result of linkage disequilibrium between HCR and PSORS1 rather than causality (Chia et al. J Invest Dermatol. 2001;116:823-824). Dr. Elder explained that linkage disequilibrium occurs when the same allele (variant) of a gene appears in apparently unrelated persons owing to distant common ancestry.

Despite the complexity of psoriatic genetics, Dr. Elder said it is important to find the associated genes so researchers can put them together into pathways. "We can get ideas about what the other genes might be by examining other gene participants in the same pathway," he said. "We'll always have our patients that we've painstakingly collected over the years, so we can go back and test these other candidate genes to see if they are present more often in cases than in controls. Up until now, most people haven't pursued candidate genes because there are simply too many of them."

Link to Autoimmunity

There may be genes that contribute not only to psoriasis but to other autoimmune diseases as well, Dr. Elder said. "In our review, we called them severity genes because rather than being a specific signature for one disease or the other, they may make you more susceptible to a variety of immune-type diseases."

Dr. Elder cited PSORS8, located on chromosome 16, as a possible example of such a gene. A gene called NOD2, which is located in the same region of chromosome 16 as PSORS8, has been implicated in Crohn's disease, a form of inflammatory bowel disease. Noting that psoriasis is present seven times more often in Crohn's disease patients than in controls, Dr. Elder said, "Despite the fact that our early studies of NOD2 in psoriasis have not implicated the same mutations found in Crohn's disease, it remains possible that some patients with psoriasis may carry different mutations in the NOD2 gene.

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