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New Psoriasis Susceptibility Genes: Momentum for Skin-Barrier Disruption

      The epidermal differentiation complex gene cluster is on chromosome region 1q21.3, where the PSORS4 locus was mapped. A common deletion of two LCE genes (LCE3C_LCE3B-del) was associated with psoriasis. Individuals homozygous for the deletion have an impaired response of the skin barrier to exogenous agents, facilitating the systemic skin inflammation characteristic of psoriasis.
      Psoriasis is a multifactorial disease in which an individual’s genetic background interacts with environmental factors to define overall risk (
      • Griffiths C.E.
      • Barker J.N.
      Pathogenesis and clinical features of psoriasis.
      ). The first proof of a strong genetic component came from the high disease concordance among twins. Familial transmission studies estimated a 41% risk for the offspring of two affected parents and a 14% risk when only one parent was affected. The genetic component affects not only overall risk, but also the age of disease onset. Serological typing of human leukocyte antigen (HLA) class I antigens identified the first locus for psoriasis (PSORS1) in the chromosome 6p21.3 region. Further studies identified a strong association between psoriasis and the HLA-Cw6*0602 allele (
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ). This HLA variant could play a role in the presentation of antigens to the CD8+ T and natural killer cells by the epidermal cells in psoriatic lesions (
      • Gudjonsson J.E.
      • Johnston A.
      • Sigmundsdottir H.
      • et al.
      Immunopathogenic mechanisms in psoriasis.
      ). Although HLA-Cw6 remains the major genetic determinant of psoriasis, recent genome-wide association studies have identified new variants in other immunocompetent genes, such as IL-12 and IL-23. These studies have contributed to our current view of psoriasis as a disease in which primary external stimuli activate the release of key cytokines by keratinocytes (
      • Elder J.T.
      • Bruce A.T.
      • Gudjonsson J.E.
      • et al.
      Molecular dissection of psoriasis: integrating genetics and biology.
      ), initiating a cascade of molecular and cellular events that include the differentiation of naive T cells to the type 1 T-helper cells (particularly the Th1 and Th17 subsets) that infiltrate psoriatic skin.
      These and other findings (e.g., the effective treatment of psoriatic patients with drugs that modulate effector lymphocytes or with antibodies against the common p40 subunit of IL-23 and IL-12) sustain the hypothesis that dysregulation of the immune response is the main primary cause of psoriasis. Factors such as abnormalities in keratinocytes and insults in the skin barrier remained secondary players. However, results from recent genetic association and functional studies have changed this scenario. In this issue of JID, Riveira-Muñoz et al. report a meta-analysis of the association between psoriasis and a common deletion (LCE3C_LCE3B-del) in the late-cornified envelope (LCE) cluster. This cluster is on chromosome region 1q21.3, where the PSORS4 locus was identified. The LCE3C_LCE3B-del was first linked to psoriasis in a genome-wide association study on individuals of European ancestry, and the association was replicated by others (
      • De Cid R.
      • Riveira-Muñoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Hüffmeier U.
      • Bergboer J.G.
      • Becker T.
      • et al.
      Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors.
      ).
      • Riveira-Muñoz E.
      • He S.-M.
      • Escaramís G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ) studied 9,389 psoriasis patients and 9,477 controls from populations of European ancestry (Finland, France, Germany, Ireland, Italy, Spain, the Netherlands, UK, and the United States) and of Asiatic origin (China, Mongolia, and Japan). The frequency of homozygotes for the deletion was significantly higher among the patients, with an overall odds ratio (OR) of 1.20 (95% confidence interval = 1.15–1.28) for the Europeans. This OR was much lower than the value attributed to the Cw6 variant but was closer to the value for other well-characterized susceptibility (e.g., IL-12 and IL-23) polymorphisms.
      The LCE proteins are part of the epidermal differentiation complex (EDC) involved in the terminal differentiation of the epidermis (
      • Mischke D.
      • Korge B.P.
      • Marenholz I.
      • et al.
      Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (“epidermal differentiation complex”) on human chromosome 1q21.
      ). LCE3C was expressed at a low to null level in normal skin, depending on the LCE3C_LCE3B-del genotype (deletion homozygotes had a complete lack of the LCE3C mRNA). In a challenging experiment, the Xavier Estivill group found a link between the deletion and an impaired skin barrier response (
      • De Cid R.
      • Riveira-Muñoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ). Removal of the stratum corneum through adhesive tape stripping promoted the hyperproliferation and differentiation of keratinocytes and an increased expression of LCE3C and other genes involved in skin barrier formation. The exception was an individual homozygous for the deletion who did not show LCE3C mRNA induction (
      • De Cid R.
      • Riveira-Muñoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ). It is well recognized that the nonlesional skin of psoriatic patients is prone to develop inflammatory lesions upon exfoliation and other mechanical stimuli (the so-called Koebner phenomenon). The obvious speculation was that the absence of intact LCE3C and LCE3B genes could lead to impaired epidermal repair after barrier disruption, making the skin more susceptible to penetration by exogenous agents. This, together with an immunological genetic background (e.g., HLA-CW6 positivity), could facilitate the development of inflammation characteristic of psoriasis.
      The LCE-del would compromise the skin barrier through a loss of function. There is a recent example of how a genetically improved EDC function could also promote inflammation, facilitating the development of psoriasis. The S100 calcium-binding proteins are encoded by genes in the PSORS4 cluster, approximately 500 Mb from the LCE cluster (
      • Jackson B.
      • Tilli C.M.
      • Hardman M.J.
      • et al.
      Late cornified envelope family in differentiating epithelia—response to calcium and ultraviolet irradiation.
      ). Like LCE proteins, the S100 proteins are components of the cornified envelopes and skin barrier. However, human S100A7 and S100A15 proteins also act as chemokines upregulated and released during skin inflammation. Their proinflammatory effects are mediated through its binding to receptors of advanced glycation end products on leukocytes. In mice, the overexpression of S100a7/a15 resulted in skin prone to inflammation, a phenomenon that resembles the histological and molecular characteristics of nonlesional psoriatic skin (
      • Wolf R.
      • Mascia F.
      • Dharamsi A.
      • et al.
      Gene from a psoriasis susceptibility locus primes the skin for inflammation.
      ). These mice were also more likely to develop skin lesions in response to proinflammatory stimuli such as skin irritants and, interestingly, exfoliation of epidermis by tape stripping.
      • Riveira-Muñoz E.
      • He S.-M.
      • Escaramís G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      observed a significant negative correlation between the frequency of LCE3C_LCE3B-del among controls and the corresponding OR for psoriasis: the more common the risk allele, the smaller its effect on psoriasis risk. In Europe, this seems to follow a north–south gradient. In our population (Asturias, northern Spain), the frequencies of deletion homozygotes in controls (n = 400) and psoriasis patients (n = 320) were 42 and 36%, respectively, with an OR of 1.30 (
      • Coto E.
      • Santos-Juanes J.
      • Coto-Segura P.
      • et al.
      Mutation analysis of the LCE3B/LCE3C genes in psoriasis.
      ). These values fit well in the frequency-risk correlation model of
      • Riveira-Muñoz E.
      • He S.-M.
      • Escaramís G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ). Although sampling error cannot be excluded, a genuine effect of this phenomenon on the genetic predisposition to psoriasis is possible and requires further investigation. The LCE3C_LCE3B-del is a functional gene variant, and it is probably responsible for the observed risk. However, a nearby functional variant in linkage disequilibrium (LD) with the deletion could also contribute to the risk of developing psoriasis. For instance, the LCE-del could be in LD with a variant that increased the expression of S100 genes; in such a case, individuals homozygous for the LCE-del and with increased S100 expression might be at the highest risk for psoriasis. Differences in haplotype frequencies among populations could thus explain the different OR values for the LCE-del. An interaction between the LCE-del and an environmental factor that had a south–north gradient could also explain the correlation between the deletion frequency and risk.
      These studies will fuel new research on other PSORS4 genes. The EDC cluster contains more than 50 genes from several families. The LCE3C_LCE3B-del is only one of the many variants that could affect the expression or function of these components. Association studies with single-nucleotide polymorphisms (SNPs) within this region will be necessary to identify other risk alleles. At least one SNP that mapped to this cluster (rs4112788) has been linked to psoriasis, but the risk allele was in almost complete LD with the LCE-del and would thus be a surrogate marker for the deletion (
      • De Cid R.
      • Riveira-Muñoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ). The resequencing of this genome region in psoriasis patients and healthy controls is necessary to identify whether other common and rare variants contribute to the risk for psoriasis. Other LCE and the S100A7 and S100A15 genes are the strongest candidates with which to start this search.
      Finally, exposure to UV radiation is usually beneficial in psoriasis, but a subset of patients develop severely photosensitive psoriasis (
      • Rutter K.J.
      • Watson R.E.
      • Cotterell L.F.
      • et al.
      Severely photosensitive psoriasis: a phenotypically defined patient subset.
      ). In these patients, UV radiation induces thickening of the stratum corneum, an effect mediated by the upregulation of LCE and other EDC genes (
      • Jackson B.
      • Tilli C.M.
      • Hardman M.J.
      • et al.
      Late cornified envelope family in differentiating epithelia—response to calcium and ultraviolet irradiation.
      ). Could the LCE-del and other EDC gene variants modify the extent of skin’s response to UV irradiation in psoriasis? A positive answer might have clinical consequences, because the genotyping of these variants could help identify patients likely to respond adversely.

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