NEWS, VIEWS & REVIEWS
Truth or Fiction: Risk Factors for Childhood Atopic Dermatitis
November 2011 | Volume 10 | Issue 11 | Feature | 1337 | Copyright © 2011
Kendra Gail Bergstrom MD
Psoriasis continues to be one of the most common and frustrating conditions that dermatologists and their patients face on a daily basis. Novel developments in basic science bring us closer than ever to understanding the pathogenesis of psoriasis. At the same time, the advent of biologic immunomodulators has opened doors in terms of treatment options and a better understanding of the underlying etiology of psoriasis. Genes involved in the immune system, keratinocyte differentiation, and vascular hyperplasia have all been implicated in psoriasis.
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It has long been understood that psoriasis has a hereditary and familial component. Psoriasis seems to be more common among some ethnic groups, with a prevalence of up to three percent in some Caucasian populations and much less than one percent among African, Asian, and South American populations. Among first-degree relatives of psoriasis patients, approximately thirty percent will have psoriasis themselves. In twin studies, monozygotic twins have a two to three times increased risk over dizygotic twins when one twin has psoriasis.
Initial work into psoriasis genetics linked psoriasis susceptibility with several genetic locations. These loci of interest were appropriately named with the acronym 'PSOR' one through six and later up to the number ten. These loci were initially quite broad and the exact gene in question wasn't always at first apparent. As genetic mapping becomes more powerful, these loci are being mapped to several immune system and cutaneous structural genes.
Psoriasis is exclusively a human disease; only two possible cases have been described in monkeys over the past fifty years and none have been described in other mammals. Several skin diseases are seen in mice, but none have all of the histologic features of psoriasis or response to the same topical and oral medications as human psoriasis. Further information on psoriasis genetics was added with the development of several animal models. Several types of genetically altered mice have been developed to mimic psoriasis. There are fundamental challenges in recreating psoriasis in mice, particularly including that mouse skin is mainly covered with hair follicles and does not normally have rete ridges between follicles.1 The latest models are xenografts, where human psoriatic skin has been grafted onto immunodeficient mice.
In human gene mapping studies among large families, several genetic loci have been associated with psoriasis. These loci are often large areas of a chromosome, so further work into determining which part of a large area is important is still being conducted. To date, at least ten loci of interest have been identified. Some loci are common to many parts of the world and others are found in only some subsets of psoriasis. Table 1 highlights the different genetic loci.
The PSORS1 locus contains several different immune system genes that are themselves closely linked, so it has been challenging for researchers to tease apart which of these genes might be implicated in psoriasis. This area of the genome encodes HLA type I molecules. The latest evidence seems to show that the HLA-C locus, in particular the Cw6 variation, is associated with a 10 to 20-fold increased risk of psoriasis compared to a general population.2 Interestingly, this association is only with classis plaque-type psoriasis of early onset, and is less associated with pustular psoriasis, palmoplantar psoriasis, or other variations. It also appears to be less well-associated with psoriatic arthritis. Most of this work has been done in northern European populations.
Other genes in the psors1 locus that may be associated with psoriasis include the attachment protein corneodesmin, and other proteins, such as CCHCR-1, whose functions are not yet understood. The corneodesmin protein itself is overrepresented in the epidermis of psoriasis, so there is speculation that it may be inhibiting normal cell detachment and desquamation.
Psors2 encodes several different genes; the catchiest of which is named “RAPTOR.” This acronym is short for regulatory associated protein of mammalian target of rapamycin. This RAPTOR gene modulates the mammalian target of rapamycin, so-called M-tor, and is part of the inflammatory pathway that is targeted by cyclosporine. Psors2 has not been associated with psoriatic arthritis in one study of Italian patients. Cyclosporine is not effective for psoriatic arthritis, so it is interesting to speculate that the pathogenesis of psoriatic arthritis could be distinct from this pathway for psoriasis.
Interferon-1 is a known trigger for psoriasis flares in humans. While there is no exact mouse model for psoriasis, mice that cannot regulate interferon-1 present with a psoriasis-like skin disease. The psors3 locus does not encode interferon-1 itself, but a key regulator called Interferon regulatory factor-2, or IRF-2.
The IRF gene was typed among a group of families in Germany with psoriasis-57 families with a total of 521 individuals.3 There were two areas of this gene that were associated with type I psoriasis, which is characterized by classic plaque psoriasis with early