Trends in Genetics
Volume 26, Issue 9, September 2010, Pages 415-423
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Review
Psoriasis genetics: breaking the barrier

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Psoriasis is a common incurable inflammatory skin disease affecting 2–3% of the European population. Psoriatic skin contains large numbers of immune cells which produce many cytokines, chemokines and inflammatory molecules. The epidermis divides much faster than normal and has a defective outer layer or barrier which under normal circumstances protects from infection and dehydration. Psoriatic skin is characterized by a distinct set of inflammation and epidermal proliferation and differentiation markers, and it has been unclear whether the genetic basis of psoriasis reflects defects of the immune system or of the skin. One genetic determinant lies within the major histocompatibility complex class 1 region. Genome-wide association studies have revealed genetic susceptibility factors that play a role in the formation of immune cells found in psoriasis lesions. Others affect epidermal proliferation and skin barrier formation. Hence, genetic components of both the immune system and the epidermis can predispose to disease.

Section snippets

Psoriasis: a common inflammatory skin disease with a genetic component

Psoriasis affects 2–3% of the European population, is less common in individuals of Asian descent (0.1% or less), and is exceedingly rare in Africa [1]. Initial outbreaks typically affect individuals in their twenties, but can occur at any age [2]. Psoriasis patients have a natural history of outbreaks (flares) followed by temporary remissions. Environmental factors can trigger or exacerbate flares. These factors include HIV infection [3], use of drugs such as lithium, beta-blockers, or

Histopathology and molecular biology of psoriasis

There are several different forms of psoriasis (Figure 1). The most common form of psoriasis, termed plaque psoriasis or psoriasis vulgaris (PV), accounts for approximately 90% of all psoriasis cases [8]. Individuals with PV also may develop lesions in response to physical trauma (termed the Koebner response [9]). This is obtained by repeatedly applying and removing a piece of tape from the individual's skin, a procedure referred to as tape stripping, which effectively disrupts the skin barrier

Pre-GWAS psoriasis genetics

Because of the inflammatory nature of psoriatic skin, it was hypothesized that its immune cells were reacting to an as-yet unidentified antigen. Hence, the earliest genetic studies on psoriasis were case/control studies performed with classical major histocompatibility complex (MHC) alleles. This revealed association with human leukocyte antigen (HLA) class 1 alleles, and the strongest association was with the HLA-C allele, Cw6[25]. In these early studies, which were performed in Northern

Inflammatory genes

Several large GWAS for psoriasis in both the European and Asian populations have been performed to date 31, 32, 33, 34, 35 and these have replicated association with several risk genes (Table 1). Interestingly, the most highly significant associations in both populations are with SNPs from the MHC class I region that encodes the HLA molecules HLAA, HLAB and HLAC. The psoriasis-associated SNPs are physically close to the gene encoding HLAC33, 34, 35 and the associated SNP alleles are highly

Psoriasis-like mouse models with barrier dysfunction

Genetic perturbations affecting mouse skin frequently result in a psoriasis-like phenotype that includes inflammation and hyperproliferation; this is consistent with the observation that keratinocyte hyperplasia, vascular hyperplasia and cell-mediated immunity in the skin are inter-related. There are many such models (reviewed elsewhere [55]) and some of these are discussed here.

Transgenic mice in which growth factors selective for keratinocytes (amphiregulin, Areg[56]), vascular endothelial

Psoriasis risk factors shared by other autoimmune or inflammatory diseases

Overlap between some psoriasis loci and those identified in other autoimmune or inflammatory diseases has been reported (Table 2). The same variant of IL23R is associated with Crohn's disease, PsA, and ankylosing spondylitis 33, 72, 73. This is consistent with the role of IL23R in Th17 cell activation and with the fact that these cells have a pathogenic role in several other inflammatory diseases including Crohn's disease and multiple sclerosis [40]. A haplotype harboring IL2 and IL21 is

Concluding remarks and future perspectives

Identifying the genetic basis of a complex disease such as psoriasis is challenging. The task is further complicated by the fact that psoriasis clearly involves an interaction between the immune system and the skin, leading early on to questions about where the primary defect resides. Although many early genetic studies were inconclusive, recent GWAS have started to identify specific genetic components of both the immune system and the epidermis that affect disease risk. Genetic risk factors

Acknowledgements

Dr. Alan Menter kindly provided psoriasis images. We thank Dr. Michelle Lowes, Dr. Michael Lovett, Cailin Joyce and Catherine Jordan for critical comments on the manuscript. The studies described here were supported in part by National Institutes of Health (NIH) grant R01 AR050266 (to A.M.B.). E.D.O.R. is supported by NIH training grant T32AR007279.

Glossary

AGR129 mice
a mouse strain engineered to have a deficiency in type I and type II interferon receptors and the recombination activating gene 2. They therefore lack functional B-cells, T-cells and have impaired innate immunity related to interferons.
Cornified envelope (CE)
a structure formed in the outermost layers of stratified squamous epithelia that provide a physical barrier against environmental insults. It is composed of several structural proteins which are irreversibly crosslinked by

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