NEWS, VIEWS & REVIEWS
Truth or Fiction: Risk Factors for Childhood Atopic Dermatitis
November 2011 | Volume 10 | Issue 11 | Features | 1337 | Copyright © November 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.
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
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
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
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