Review
The Pathogenesis and Genetics of Psoriasis
Psoriasis: bases genéticas y patogenéticas
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En la figura superior se representan los valores de significación estadística en relación a su posición cromosómica. Este tipo de gráfico se conoce como gráfico «Manhattan», puesto que las regiones de alta significación estadística se asemejan a la vista de una ciudad con rascacielos. En este caso, los estudios de replicación confirmaron la asociación de 7 regiones marcadas en el gráfico de color verde. En el gráfico inferior, conocido como «QQplot», se ordenan los valores de significación (esto es, <span class="elsevierStyleItalic">observed P-value</span>) y se comparan con la distribución teórica en ausencia de asociación (es decir, <span class="elsevierStyleItalic">expected P-value</span>). Este gráfico permite inspeccionar rápidamente la existencia de SNP asociadas a la enfermedad ya que, en ausencia de asociación, los valores deberían situarse sobre la diagonal. En este caso se puede observar cómo el QQplot que incluye las SNP de la región HLA (rojo) se desvía claramente. Al excluir esta región (naranja) y las otras regiones asociadas (azul) se puede ver cómo el gráfico se aproxima al valor esperado (zona sombreada). En ambos gráficos la significación para la región HLA-C se ha truncado para facilitar la interpretación de los resultados.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fuente: Elder et al.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>; Nair et al<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>. GWAS: Genomewide Association Studies; CASP: Collaborative Association Study of Psoriasis.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Puig, A. Julià, S. Marsal" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Puig" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Julià" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Marsal" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1578219014001486" "doi" => "10.1016/j.adengl.2014.05.013" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001486?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731012005431?idApp=UINPBA000044" "url" => "/00017310/0000010500000006/v1_201406280127/S0001731012005431/v1_201406280127/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S1578219014001516" "issn" => "15782190" "doi" => "10.1016/j.adengl.2014.05.016" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "973" "copyright" => "Elsevier España, S.L. and AEDV" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2014;105:546-57" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5858 "formatos" => array:3 [ "EPUB" => 41 "HTML" => 4493 "PDF" => 1324 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Cutaneous Manifestations in Children with Diabetes Mellitus and Obesity" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "546" "paginaFinal" => "557" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Manifestaciones cutáneas en niños con diabetes mellitus y obesidad" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 744 "Ancho" => 980 "Tamanyo" => 100585 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Follicular hyperkeratotic papules secondary to keratosis pilaris on the buttocks, accompanied by striae.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. 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Puig, A. Julià, S. Marsal" "autores" => array:3 [ 0 => array:4 [ "nombre" => "L." "apellidos" => "Puig" "email" => array:1 [ 0 => "lpuig@santpau.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A." "apellidos" => "Julià" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "S." "apellidos" => "Marsal" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Grup de Recerca de Reumatologia, Institut de Recerca Vall d’Hebron, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Psoriasis: bases genéticas y patogenéticas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1504 "Ancho" => 3088 "Tamanyo" => 223609 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Summary of the results of the Genome Wide Association Study known as the Collaborative Association Study of Psoriasis. The top plot shows the statistically significant values in relation to the chromosomal position. This type of plot is known as a Manhattan plot, as the highly significant regions resemble the skyline of a city with skyscrapers. In this case, the replication studies confirmed the association of 7 regions marked in the green plot. The lower plot, known as a QQplot, orders the values by significance (that is, observed <span class="elsevierStyleItalic">P</span> value) and compares them with the theoretical distribution in absence of an association (that is, expected <span class="elsevierStyleItalic">P</span> value). Such a plot readily reveals the existence of single nucleotide polymorphism (SNPs) associated with the disease as, in absence of any association, the values appear on the diagonal line. In this case, we see how the QQplot of the SNP of the human leukocyte antigen (HLA) region (in red) deviates clearly. When this region (orange) and the other associated regions (blue) are excluded, we see how the plot approaches the expected value (shaded zone). In both plots, the significance of the HLA-C region is truncated to facilitate interpretation of the results.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Source: Elder et al.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>; Nair et al.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Abbreviation: MHC, major histocompatibility complex.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Evidence suggests that psoriasis vulgaris is not a genetically homogenous disease but rather several different disease phenotypes associated with different genetic variants. For example, purely palmoplantar pustulosis can be considered a separate entity from psoriasis vulgaris, which in turn is genetically more closely associated with guttate psoriasis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Psoriasis vulgaris is a chronic inflammatory disease that shows a clear association with certain alleles of the <span class="elsevierStyleItalic">HLA-C</span> gene, and specifically with the <span class="elsevierStyleItalic">HLA-Cw6</span> allele (known as <span class="elsevierStyleItalic">HLA-Cw*0602</span> when identified through high-resolution genotyping), present in 30% of psoriasis patients (compared with between 10% and 15% in the general population). The relative risk of developing the disease is 2.5 greater in homozygous individuals than in heterozygous ones.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleItalic">HLA-Cw6</span>-positive patients have certain clinical characteristics defined by an early onset of the disease, presence of more extensive plaques, and a higher incidence of the Koebner phenomenon. In addition, more frequent streptococcal throat infection and high sensitivity to sunlight may be trigger factors and markers of more severe disease. <span class="elsevierStyleItalic">HLA-Cw6</span>-negative patients, in contrast, have a higher frequency of nail disorders and psoriatic arthritis.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Before detailing the most important genetic aspects of the disease, we will review the underlying immunopathogenic mechanisms to enable a more integrated overview of the major therapeutic advances in recent years. These advances will then be described in detail.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Immunopathogenesis of Psoriasis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Psoriasis is characterized by marked epidermal proliferation and abnormal differentiation with immune activation of keratinocytes, accompanied by numerous inflammatory and immune disorders, in which both innate and acquired immunity participate.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a> The efficacy of cyclosporin, demonstrated more than 25 years ago, pointed to the fundamental role of T-lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Subsequently, the efficacy of selective T-cell modulators further confirmed the importance of these types of cells.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–10</span></a> The marked efficacy of biologic agents that target tumor necrosis factor alfa (TNF-α) has also been demonstrated recently.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> This cytokine acts as a pleiotropic mediator of different types of inflammation. Likewise, anti-p40 antibodies, which block differentiation and expansion of Th1 and Th17 lymphocytes through interleukin (IL) 12 and IL-23, respectively, have also been found to be effective.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The role of TNF-α and skin-resident T-lymphocytes has been confirmed in an experimental model with AGR129 mice, which lack the genes that encode interferon (IFN) and natural-killer (NK) cells, and so are unable to reject human skin.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> When apparently healthy skin from patients with psoriasis was grafted onto these mice, they spontaneously developed psoriasis plaques without the addition of CD4<span class="elsevierStyleSup">+</span> T lymphocytes. Serial biopsies showed that human T lymphocytes resident in the grafts proliferate and produce TNF-α, and treatment with human anti-CD3 antibodies, which impede T-lymphocyte proliferation, or TNF-α inhibitors (infliximab or etanercept), prevented conversion of the prepsoriatic skin into psoriasis lesions.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Moreover, blockade of the exocytosis of T lymphocytes to the epidermis with an anti-integrin α1β1 antibody limits lesion development. When T lymphocytes are already present in the epidermis, inhibition is partial, and treatment is ineffective when fully developed psoriasis lesions are grafted, thereby confirming the role of resident T lymphocytes and their migration to the epidermis in the development of psoriasis lesions.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The recent discovery of a subpopulation of T lymphocytes that express IL-17, and whose expression is determined by the action of IL-23 produced by antigen-presenting cells and dendritic cells on naïve T-cell precursors,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> has greatly changed our understanding of the pathogenesis of psoriasis. A marked expansion of cytotoxic T lymphocytes, which independently express IL-17 and IL-22 in the psoriatic epidermis, has been reported.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16,17</span></a> The expansion of Th1 lymphocytes feeds back into this process by stimulating synthesis of IL-12 and IL-23 by antigen-presenting cells through production of IFN-γ.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Genetic Linkage Studies of Psoriasis</span><p id="par0030" class="elsevierStylePara elsevierViewall">In the 1990s, several groups started gene linkage studies which analyzed the cosegregation of microsatellite genetic markers in families with members with psoriasis. At least 6 loci of susceptibility to psoriasis, denoted PSORS1 through PSORS6, were identified.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18–21</span></a> The main genetic determinant of psoriasis (PSORS1), located in the 6p21 chromosomal region, accounts for between 30% and 50% of genetic susceptibility to the disease and probably corresponds to the <span class="elsevierStyleItalic">HLA-Cw*0602</span> allele, although the determinant is not associated with cases of late-onset psoriasis.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> This allele has been postulated to allow the presentation of a putative epitope present in type-I keratins, specifically, those whose expression is upregulated in psoriasis. This epitope may act as an autoantigen, present cross-reactivity with streptococcal protein M, and perpetuate autoimmune response (and perhaps CD4<span class="elsevierStyleSup">+</span> response with NK receptors) mediated by CD8<span class="elsevierStyleSup">+</span> cells, which are able to recognize the major histocompatibility complex (MHC) class I, leading to chronic lesions.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The second locus of susceptibility to psoriasis, PSORS2, identified through linkage studies in different families, is located in the 17q24-q25 region, where a susceptibility locus has also been identified for atopic dermatitis, and the putative genes are implicated in regulating the immunological synapsis.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,21</span></a> Linkage studies in families from different geographic regions have identified other loci (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), such as PSORS3 (4q34), PSORS4 (1q21), PSORS5 (3q21), PSORS6 (19p13), PSORS7 (1p32), and PSORS9 (4q31), while others are under investigation.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21,22</span></a> Linkage with PSORS1 is clearly the most important, however. Recently, the <span class="elsevierStyleItalic">HLA-Cw6</span> allele has been confirmed as the locus responsible for the association in PSORS1,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and this finding has been confirmed in an extensive study of an ethnically diverse population.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Genome-Wide Association Studies in Psoriasis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The recent development of genetic studies based on analyzing millions of polymorphisms in a single nucleotide (single nucleotide polymorphisms [SNP]) used as genetic markers, systematic mapping of human haplotypes, and the development of high performance genotyping platforms has enabled genome-wide association studies (GWAS). In GWAS, thousands or even millions of SNP markers are analyzed in each individual, such that they account for<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>90% of the common variation present in the human genome. Given that a large number of markers are analyzed, and often the genetic effects are moderate (odds ratio [OR]<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>2), these types of genetic study require large cohorts of patients and controls. In the case of psoriasis, the main loci defined by a genetic effect with an OR><span class="elsevierStyleHsp" style=""></span>1.25 are <span class="elsevierStyleItalic">HLA-C, IL12B, IL23R, IL23A, IL4/IL13, TNFAIP3</span>, <span class="elsevierStyleItalic">TNIP1</span>, <span class="elsevierStyleItalic">TRAF3IP2</span>, <span class="elsevierStyleItalic">TYK2</span>, and <span class="elsevierStyleItalic">IFIH</span>, although other loci are in the process of being identified and validated (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Some of these loci associated with psoriasis have also been found to confer susceptibility to other inflammatory diseases of an immune nature, and are suggestive in other cases of ethnic variations in the disease.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">GWAS have provided genetic evidence of the implication of the IL-23 pathway in psoriasis. The first large-scale study of genetic association in psoriasis (which was not a GWAS in the strict sense because it only analyzed SNPs within or close to genes, but not in other regions of the genome) enabled identification of an SNP located in the 3’ terminal region of the <span class="elsevierStyleItalic">IL12B</span> gene. This gene encodes the p40 subunit common to IL-12 and IL-23, and was the first locus clearly and reproducibly associated with psoriasis risk and that was independent of major histocompatibility complex (MHC).<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> A subsequent study has managed to identify a second polymorphism independently associated with the disease. In turn, 2 other SNPs have been identified in the locus that encodes one of the subunits of the IL-23 receptor (<span class="elsevierStyleItalic">IL23R</span>), and that also shows an independent association with psoriasis.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The association of these loci has been validated in different population groups,<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29–31</span></a> both in psoriasis and in psoriatic arthritis.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32,33</span></a> Likewise, the <span class="elsevierStyleItalic">IL23A</span> gene, which encodes the p19 subunit of IL-23, has been shown to be associated with psoriasis and psoriatic arthritis<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> as well as with ankylosing spondylitis and Crohn disease, but not with rheumatoid arthritis and celiac disease.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The second GWAS published confirmed the association of genes <span class="elsevierStyleItalic">IL12B</span> and <span class="elsevierStyleItalic">IL23R</span> with psoriasis and also with psoriatic arthritis.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> The study identified a new signal close to the <span class="elsevierStyleItalic">IL23RB2</span> gene, as well as new candidate loci in the 13q13 region, which contains the <span class="elsevierStyleItalic">COG6</span> and <span class="elsevierStyleItalic">LHFP</span> genes; the 15q21 region, which contains the <span class="elsevierStyleItalic">TNFAIP8L3</span> gene; the 4q27 region, which contains the <span class="elsevierStyleItalic">IL2</span> and <span class="elsevierStyleItalic">IL21</span> genes; and the 1q21 region, which contains the <span class="elsevierStyleItalic">LCE1C</span> gene. However, the small sample size used in this study did not permit unequivocal association of these genes with psoriasis.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A GWAS, with analysis of both SNP and copy number variants (CNV), conducted in a large Chinese population of Han and Uygur ancestry,<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> identified a new association with the cluster of genes of the late cornified envelope (LCE) on chromosome 1q21, previously identified as PSORS4 through gene linkage studies. The products encoded by the genes in this region participate in the terminal differentiation of the epidermis, making these genes excellent candidates to explain the different phenotypes of psoriasis. A study published at the same time identified a CNV also associated with psoriasis in this same chromosomal region. This CNV is a deletion (that is, a DNA segment is absent) and it correlates strongly (that is, there is a linkage imbalance) with SNP rs4112788 but not with SNP rs6701216, as published by Liu et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> The association of SNP correlated with <span class="elsevierStyleItalic">LCE3C_LCE3B-del</span> was confirmed in a population of British patients with psoriatic arthritis,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> but not in a population of German patients.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In this case, the phenotypic heterogeneity of each cohort and the small sample size might explain the differences observed.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Genes do not act in isolation but operate through complex molecular networks and participate in different cellular pathways. Likewise, the association of certain genetic variants with the risk of developing the disease may be conditioned by the presence of other variants within the genome. Gene interaction, or epistasis, is a complex genetic mechanism, and until recently there was little evidence that such processes were operating in humans. It is relevant to note that the main evidence for the existence of epistasis in human diseases comes from psoriasis. In a Chinese population, the presence of epistatic interactions between the MHC and other risk genes, such as <span class="elsevierStyleItalic">LCE</span> and <span class="elsevierStyleItalic">IL12B</span>, was identified.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> The risk of psoriasis increases 26-fold in individuals with the risk alleles in <span class="elsevierStyleItalic">MHC</span> and <span class="elsevierStyleItalic">LCE</span> and 36-fold in individuals with risk alleles in <span class="elsevierStyleItalic">MHC</span> and <span class="elsevierStyleItalic">IL12B</span>, compared to individuals who are not carriers. However, in a study conducted in a population from the north of China, the investigators observed that association with <span class="elsevierStyleItalic">LCE3C_LCE3B-del</span> depends on the age of onset and the family history of the patient, and epistasis (modification of susceptibility) with the <span class="elsevierStyleItalic">HLA-Cw6</span> allele was not detected.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In 2006, investigators at the University of Michigan, the University of Washington in Saint Louis, and the University of Utah initiated a collaboration to carry out GWAS in psoriasis. In 2009, the consortium published the findings of the first GWAS, known as the Collaborative Association Study of Psoriasis (CASP). In the study, 438 670 SNPs from 1409 cases and 1436 controls were genotyped in a first phase, which was followed by genotyping of the 21 SNPs with strongest statistical evidence of an association, corresponding to 18 loci, in an independent cohort of 5048 cases and 5041 controls.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> For 10 loci, the study found evidence of association (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 in the follow-up cohort) which was especially convincing (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.0005 in the follow-up cohort) for 7 of these, confirming the association with <span class="elsevierStyleItalic">HLA-Cw6</span>, <span class="elsevierStyleItalic">IL13</span>, <span class="elsevierStyleItalic">IL12B</span>, and <span class="elsevierStyleItalic">IL23R</span>, and identifying the aforementioned association with <span class="elsevierStyleItalic">IL23A</span>. A novel finding of this study was the association of 2 genes with the signaling factor pathway for the transcription factor NF-κB (implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis): <span class="elsevierStyleItalic">TNF-α-induced protein 3</span> (<span class="elsevierStyleItalic">TNFAIP3</span>) and <span class="elsevierStyleItalic">TNFAIP3-interacting protein 1</span> (<span class="elsevierStyleItalic">TNIP1</span>). The study did not find differences in terms of associations with psoriatic arthritis, unlike other studies in which <span class="elsevierStyleItalic">IL13</span> seems to be specifically associated with psoriatic arthritis.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35,40</span></a> Recently, investigators have published several GWAS in independent populations that confirm the association of the <span class="elsevierStyleItalic">TRAF3IP2</span> gene with both psoriasis and psoriatic arthritis.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41,42</span></a> This gene encodes a protein that disrupts IL-17-induced signal and interacts with different members of the family of Rel/NF-κB transcription factors.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Other signals have been repeatedly detected in different populations through GWAS or SNP.<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43–45</span></a> Examples include a locus close to the <span class="elsevierStyleItalic">ZNF313/RNF114</span> gene, on 20q13, which, like <span class="elsevierStyleItalic">TNFAIP3</span> and <span class="elsevierStyleItalic">TNIP1</span>, encodes a ubiquitin ligase,<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> or the regions of the <span class="elsevierStyleItalic">CDKAL1</span>, <span class="elsevierStyleItalic">PTPN22</span>, and <span class="elsevierStyleItalic">ADAM33</span> genes,<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> which have been confirmed in the case of the former.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> This locus is also implicated in susceptibility to type 2 diabetes mellitus and Crohn disease.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48,49</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">One of the most recent studies to be published reinforces the hypothesis that the pathogenesis of psoriasis combines genetic determinants of epidermal barrier dysfunction with disrupted regulation of innate and adaptive immunity. The Genetic Analysis of Psoriasis Consortium and Wellcome Trust Case Control Consortium 2 conducted a GWAS with 594 224 SNPs in 2622 patients with psoriasis and 5667 controls. The association with <span class="elsevierStyleItalic">TRAF3IP2</span> was confirmed, and 7 new loci that contained genes with immune function were identified<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>: <span class="elsevierStyleItalic">IL28RA</span>, <span class="elsevierStyleItalic">REL</span>, <span class="elsevierStyleItalic">IFIH1</span>, <span class="elsevierStyleItalic">ERAP1</span>, <span class="elsevierStyleItalic">NFKBIA</span>, and <span class="elsevierStyleItalic">TYK2</span>. These associations were validated in a replication cohort of 9079 samples from European Caucasian individuals.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> The study identified the epistatic association of the <span class="elsevierStyleItalic">HLAC</span> and <span class="elsevierStyleItalic">ERAP1</span> genes with the risk of developing psoriasis. The <span class="elsevierStyleItalic">ERAP1</span> gene product participates in the processing of peptides by class <span class="elsevierStyleSmallCaps">i</span> MHC and the risk allele for this gene only increases the risk of psoriasis in those individuals who are positive for the <span class="elsevierStyleItalic">HLA-Cw*0602</span> allele.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> This is one of the first clear and reproducible examples of epistasis in humans.</p><p id="par0075" class="elsevierStylePara elsevierViewall">A recent GWAS replication study,<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> performed in China,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> and including 8312 patients with psoriasis and 12 919 Chinese controls, 3293 cases and 4188 controls in German and the United States, and 254 nuclear families in the United States, identified 6 new susceptibility loci that contained gene candidates <span class="elsevierStyleItalic">ERAP1, PTTG1, CSMD1, GJB2, SERPINB8</span>, and <span class="elsevierStyleItalic">ZNF816A</span>, which replicated a locus on 5q33.1 (<span class="elsevierStyleItalic">TNIP1-ANXA6</span>), previously reported in European studies. Two of the loci identified (<span class="elsevierStyleItalic">ZNF816A</span> and <span class="elsevierStyleItalic">GJB2</span>) also show evidence of an association in a study of the German population. Moreover, <span class="elsevierStyleItalic">ERAP1</span> and <span class="elsevierStyleItalic">ZNF816A</span> are associated with type 1 psoriasis (that is, early-onset psoriasis) in Chinese individuals of Han ancestry. Apart from identifying new factors of genetic susceptibility, this study clearly illustrates that part of the genetic heterogenicity present in the disease can be attributed to genetic differences between ethnically different populations.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The results of different GWAS can be pooled to increase statistical power and thus identify new risk loci. Recently, a metaanalysis of 2 of the aforementioned GWAS and a more recent third GWAS conducted in a new cohort of 1831 cases and 2546 controls and replicated in 4064 cases and 4685 controls in Michigan, Toronto, Terranova, and Germany,<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> identified 3 new susceptibility loci, <span class="elsevierStyleItalic">NOS2</span>, <span class="elsevierStyleItalic">FBXL19</span>, and one near <span class="elsevierStyleItalic">PSMA6-NFKBIA</span>. All these were associated with both cutaneous psoriasis and psoriatic arthritis. Likewise, in this study, the association of a signal near <span class="elsevierStyleItalic">RNF114</span>, described recently, was replicated.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49,51</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Integrative Concept of the Genetic Component and Immunopathogenesis of Psoriasis</span><p id="par0085" class="elsevierStylePara elsevierViewall">As illustrated by the results of the CASP study (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>), the MHC is the main determinant of genetic susceptibility in psoriasis. Several SNPs in the region of the MHC have been associated with psoriasis in different GWAS. The SNP with the strongest association, rs1219187, shows a marked linkage imbalance with the <span class="elsevierStyleItalic">HLA-Cw*0602</span> allele,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> the main risk allele,<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> but other independent signals are present such as rs2022544,<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> rs2073048, located on <span class="elsevierStyleItalic">c6orf10</span>, a potential mediator in the TNF-α pathway, and rs13437088, at 30<span class="elsevierStyleHsp" style=""></span>kb<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> from HLA-B in the centromere direction and at 16<span class="elsevierStyleHsp" style=""></span>kb from <span class="elsevierStyleItalic">MICA (M</span>HC class I polypeptide-related sequence A precursor) in the telomere direction.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> A detailed analysis in 2 Chinese populations of Han ancestry has identified an association of <span class="elsevierStyleItalic">HLA-B*57</span> with an increased risk of psoriasis, and of <span class="elsevierStyleItalic">HLA-B*40</span> with a decreased risk of disease, independently of <span class="elsevierStyleItalic">HLA-Cw*0602</span> and the <span class="elsevierStyleItalic">C6orf10</span> locus.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> The second association was validated recently in a study that showed that <span class="elsevierStyleItalic">MICA*016</span> increased the risk of developing psoriasis without arthritis, and homozygosity for <span class="elsevierStyleItalic">MICA*00801</span> increased the risk of developing the arthritic form of the disease in patients with psoriasis.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Guttate psoriasis, which is associated with <span class="elsevierStyleItalic">HLACw6</span> in up to 100% of cases,<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> is often preceded by streptococcal throat infection (rarely by perianal dermatitis, balanoposthitis, or vulvovaginitis), and infrequently by other streptococcal infections of the skin such as impetigo and erysipelas. During the course of the throat infection, <span class="elsevierStyleItalic">HLA-Cw6</span>-mediated streptococcal antigens or superantigens are presented to the naïve tonsillar T lymphocytes that will proliferate and differentiate into an effector phenotype and a memory phenotype, and acquire a skin homing capacity (CLA+),<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,54</span></a> whereas the peptidoglycan of the streptococcal wall could alternatively activate lymphocytes by activating cytokine-mediated Toll-like receptors.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> With time, oligoclonal expansion of the T lymphocytes directed against streptococcal antigens with skin homing will occur. These cells will begin to recognize epidermal autoantigens, giving rise to the plaque psoriasis lesions.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> The genetic predisposition determined by <span class="elsevierStyleItalic">HLA-Cw6</span> and other components of the MHC may arise through loss of tolerance to epidermal autoantigens, especially if their expression is upregulated or they appear (neoantigens) in psoriasis. This is the case for a range of proteins, such as K16 and K17 keratins, β-defensin-4 (encoded by <span class="elsevierStyleItalic">DEFB4</span>), psoriasin (S100A7), calgranulin (S100A8 and S100A9), small proline-rich region proteins (SPRR), and CLE proteins, many of which are encoded in the epidermal differentiation complex located on 1q21.3 (PSORS4). Genes that encode human β-defensins (antimicrobial peptides with similar activity to cytokines) are located in several clusters. One of them located on the 8p23-1 region has recently been associated with an amplification-type CNV of the <span class="elsevierStyleItalic">DEFB4</span>, <span class="elsevierStyleItalic">DEFB103</span>, and <span class="elsevierStyleItalic">DEFB104</span> genes, which encode the β-defensins 4, 3, and 2, respectively.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Given that the vast majority of T lymphocytes in the psoriatic infiltrate do not show clonal expansion, other antigen-independent mechanisms must be in operation. In these mechanisms, HLA-C may also participate, acting as a ligand for the killer immunoglobulin-like receptors (KIR). These receptors regulate the activity of the NK-T cells and are encoded by the <span class="elsevierStyleItalic">KIR</span> gene, whose locus is associated with psoriasis and psoriatic arthritis.<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61–65</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Another important genetic determinant of psoriasis presumably relates to regulation of the NF-kB signaling pathway (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>). A20 and ABIN1, which are <span class="elsevierStyleItalic">TNFAIP3</span> and <span class="elsevierStyleItalic">TNIP1</span> gene products, respectively, participate in ubiquitin-mediated destruction of the IKKγ/NEMO complex and other components of the TNF-α signal transduction pathways. Recently, murine models have been developed with specific suppression of A20 expression in the skin and macrophages that develop psoriasiform dermatitis<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> and arthritis.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> These experimental models confirm the importance of this pathogenic pathway in psoriasis and the role of A20 as an inhibitor of the activation of dendritic cells and autoimmune response.<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">68,69</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Abnormal transcription of cytokines in the Th2 family (IL-13, IL-4, IL-5) may interfere with the negative regulation of differentiation of naïve T lymphocytes to Th17 lymphocytes<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> and with IL-17 synthesis by these cells.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> Interestingly, although signals related to the <span class="elsevierStyleItalic">IL-13</span> gene have been identified along with the cluster that regulates the transcription of different Th2 cytokines in different studies,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> this association has recently been found to be limited to patients with psoriatic arthritis.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Recent Advances</span><p id="par0110" class="elsevierStylePara elsevierViewall">As proof of the dynamic nature of genetic study in psoriasis, and by way of conclusion, we only need cite the 2 most recent advances in this field, which are related to monogenic forms of pustular psoriasis.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Generalized pustular psoriasis is characterized by repetitive episodes of generalized pustular rash accompanied by high fever, leukocytosis, and elevated levels of C reactive protein. Plaque psoriasis may also be present. A hereditary form has been reported with autosomal recessive transmission. A study of 9 Tunisian families with this disease identified linkage with a 1.2 megabase region on 2q13-q14.1 and a homozygous mutation in the <span class="elsevierStyleItalic">IL36RH</span> gene, which encodes the receptor antagonist for IL-36 (a cytokine with anti-inflammatory properties) and which is responsible for defective synthesis of a less stable and less potent variant in terms of interaction with IL1 receptor-like 2. This mutation leads to an increase in the production of IL-8 and other pro-inflammatory cytokines by keratinocytes, in turn leading to intraepidermal accumulation of polymorphonuclear molecules.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> Other mutations of the same gene have been identified in 3 sporadic cases of the same disease,<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> which has become known as deficiency of the IL-36R antagonist (DITRA) and which bears strong resemblance to deficiency of the IL-1R antagonist (DIRA), an autoinflammatory disease reported in 2009 with strong response to treatment with IL-1 antagonists such as anakinra.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Another significant advance was the identification of the <span class="elsevierStyleItalic">CARD14</span> gene as responsible for the association with PSORS2 when mutations leading to increased function of the transcribed protein (caspase recruitment domain-containing protein 14) were found in 2 extended families, one in Europe with multiple cases of psoriasis and psoriatic arthritis in 30% of them and another in Taiwan, as well as a de novo mutation in a girl with early-onset sporadic pustular psoriasis.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> In another article, published by the same group, 15 additional variants of <span class="elsevierStyleItalic">CARD14</span> are described along with their distribution in 7 cohorts of patients with psoriasis (more than 6000 cases and controls). These variants are suggestive of epistasis with <span class="elsevierStyleItalic">HLA-Cw6</span> and their effect on activation of NF-κB and the transcription of different genes in keratinocytes transfected with different mutants.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> Caspase recruitment domain-containing protein 14 is usually localized to the basal and suprabasal layers of the epidermis, whereas expression in psoriatic lesions is upregulated in diffuse and localized fashion in the suprabasal layers. <span class="elsevierStyleItalic">CARD14</span> mutations associated with the development of psoriasis lead to increased activation of NF-κB and the expression of different genes associated with psoriasis in keratinocytes.</p><p id="par0125" class="elsevierStylePara elsevierViewall">In both cases, these findings reinforce the current hypothesis for pathogenesis linked to the role of keratinocytes in psoriasis, and extend our knowledge of the mechanisms of production of pustular lesions, as well as the exceptional monogenic forms of the disease.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Ethical Responsibilities</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protection of human and animal subjects</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Confidentiality of data</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that patient data do not appear in this article.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Right to privacy and informed consent</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that patient data do not appear in this article.</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">This manuscript was drafted as part of the Strategic Project PSE-010000-2006-6, funded by the Ministry of Science and Innovation.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of Interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres349110" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec330776" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres349109" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec330775" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Immunopathogenesis of Psoriasis" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Genetic Linkage Studies of Psoriasis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Genome-Wide Association Studies in Psoriasis" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Integrative Concept of the Genetic Component and Immunopathogenesis of Psoriasis" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Recent Advances" ] ] ] 9 => array:3 [ "identificador" => "sec0035" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of Interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-07-01" "fechaAceptado" => "2012-11-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec330776" "palabras" => array:4 [ 0 => "Genetics" 1 => "Pathogenesis" 2 => "Psoriasis" 3 => "Psoriatic arthritis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec330775" "palabras" => array:4 [ 0 => "Genética" 1 => "Patogenia" 2 => "Psoriasis" 3 => "Artritis psoriásica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Psoriasis vulgaris and psoriatic arthritis are interrelated disorders with an important genetic component. While linkage studies have identified several candidate <span class="elsevierStyleItalic">loci</span> and genes, only recent technological advances and extensive genome-wide association studies have provided robust evidence of associations between psoriasis and several genes inside and outside the major histocompatibility complex. Most of these genes can be incorporated into an integrated pathogenic model of psoriatic disease comprising distinct signaling networks affecting skin barrier function (LCE3, DEFB4, GJB2), innate immune responses involving nuclear factor-κB signaling (TNFAIP3, TNIP1, NFKBIA, REL, FBXL19, TYK2, NOS2, CARD14), and adaptive immune responses involving CD8 T cells and interleukin 23 (IL-23)/IL-17-mediated lymphocyte signaling (HLA-C, IL12B, IL23R, IL23A, TRAF3IP2, ERAP1). A better understanding of the potential gene/gene and gene/environment interactions and of the functions of altered transcripts will undoubtedly have nosologic, therapeutic and prognostic implications.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La psoriasis vulgar y la artritis psoriásica son trastornos relacionados entre sí, con un importante componente genético. Aunque los estudios de ligamiento han llevado a la identificación de diversos <span class="elsevierStyleItalic">loci</span> y genes de susceptibilidad, ha sido el reciente progreso tecnológico y la realización de estudios de asociación genómica extensos lo que ha permitido demostrar asociaciones robustas de la psoriasis con diversos genes, asociados o no al complejo mayor de histocompatibilidad. La mayoría de estos genes se pueden incorporar en un modelo patogénico integrado que comprende distintas redes de señalización que afectan la función barrera de la piel <span class="elsevierStyleItalic">(LCE3, DEFB4, GJB2)</span>, la respuesta inmune innata implicando al sistema de señales del factor nuclear-κB <span class="elsevierStyleItalic">(TNFAIP3, TNIP1, NFKBIA, REL, FBXL19, TYK2, NOS2, CARD14)</span>, y la respuesta inmune adaptativa implicando a linfocitos T CD8 y las señales de la vía interleucina 23 (IL-23)/IL-17 <span class="elsevierStyleItalic">(HLA-C, IL12B, IL23R, IL23A, TRAF3IP2, ERAP1)</span>. La mejor comprensión de las potenciales interacciones entre los genes implicados y de estos con factores ambientales, así como el conocimiento de las alteraciones en las funciones de las proteínas codificadas tendrán sin duda implicaciones nosológicas, terapéuticas y pronósticas.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Puig L, Julià A, Marsal S. Psoriasis: bases genéticas y patogenéticas. Actas Dermosifiliogr. 2014;105:535–545.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1504 "Ancho" => 3088 "Tamanyo" => 223609 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Summary of the results of the Genome Wide Association Study known as the Collaborative Association Study of Psoriasis. The top plot shows the statistically significant values in relation to the chromosomal position. This type of plot is known as a Manhattan plot, as the highly significant regions resemble the skyline of a city with skyscrapers. In this case, the replication studies confirmed the association of 7 regions marked in the green plot. The lower plot, known as a QQplot, orders the values by significance (that is, observed <span class="elsevierStyleItalic">P</span> value) and compares them with the theoretical distribution in absence of an association (that is, expected <span class="elsevierStyleItalic">P</span> value). Such a plot readily reveals the existence of single nucleotide polymorphism (SNPs) associated with the disease as, in absence of any association, the values appear on the diagonal line. In this case, we see how the QQplot of the SNP of the human leukocyte antigen (HLA) region (in red) deviates clearly. When this region (orange) and the other associated regions (blue) are excluded, we see how the plot approaches the expected value (shaded zone). In both plots, the significance of the HLA-C region is truncated to facilitate interpretation of the results.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Source: Elder et al.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>; Nair et al.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Abbreviation: MHC, major histocompatibility complex.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2214 "Ancho" => 3261 "Tamanyo" => 453964 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A, Main pathogenic pathways in psoriasis with genetic implications: the myeloid dendritic cells produce interleukin (IL)-12 and IL-23 after activation by different cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-α, IFN-γ, and IL-6. Naïve T lymphocytes, in presence of tumor growth factor (TGF) β, IL-6, IL-1, and IL-21, differentiate into Th17 lymphocytes, which express the IL-23 receptor and proliferate in the presence of this cytokine. Th17 lymphocytes produce IL-17A, IL-17F, IL-22, and IL-21, which activate the keratinocytes in immunologic and proliferative terms, giving rise to the production of TNF-α, IL-1, IL-6, IL-8, S100A7, and other S100 proteins and antimicrobial peptides (β-defensins). A. The binding of TNF-α to its receptor activates a cascade of signals that give rise to the release of nuclear factor (NF)-κB from its inhibitory complex NF<span class="elsevierStyleItalic">κ</span>B essential modulator/inhibitor of <span class="elsevierStyleItalic">κ</span>B kinase (NEMO/IKK), leading to transcription of A20, a negative regulator of NFκB enhanced by the ABIN-1 protein. Psoriasis is associated with certain polymorphisms in the genes that encode these 2 inhibitory proteins. B. Inhibition of IL-23-mediated signaling is the mechanism of action of the p40 inhibiting monoclonal antibodies, such as ustekinumab. Psoriasis has also been associated with polymorphisms in the genes that encode the P19 and p40 subunits of IL-23 and IL-12/IL-23, respectively, as well as a subunit of the IL-23 receptor. C. An association has been reported between the CNVs of the LCE proteins and human β-defensins and psoriasis. Abbreviations: CNV, copy number variants; LCE, late cornified envelope; MDC, myeloid dendritic cells.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Source: Adapted from Duffin et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Source: Adapted from Duffin et al.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Locus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Region \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">OMIM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Candidate Genes/Function \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6p21.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">612410</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">HLA-Cw6</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17q25.5-qter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607211</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CARD14</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4q34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">601454</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IRF-2</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1q21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">603935</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Loricrin, filaggrin, Pglyrp3,4; S100 and late cornified envelope genes (in the epidermal differentiation complex) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3q21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">604316</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">SLC12A8</span>, cystatin A, zinc finger protein 148 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19p13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">605364</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">JunB</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1p \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">605606</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PTPN22</span> (1p13), <span class="elsevierStyleItalic">IL23R</span> (1p32.1-31.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS8/PSORSA1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16q \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">610707</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CX3CL1, CX3R1, NOD2/CARD15</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4q31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607857</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL15</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18p11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">612410</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5q31-q33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">612599</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL12B</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20q13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">612950</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">ZNF313/RNF114</span>, ubiquitin ligase \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSORS13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6q21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">614070</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TRAF3IP2</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab521028.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Loci Associated With Psoriasis (PSORS) and Psoriatic Arthritis (PSORSA).</p>" ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The corresponding references are given in the text.</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: GWAS, genome wide association studies; MHC, major histocompatibility complex; SNP, single nucleotide polymorphism.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Candidate Gene \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Region/Superposition With PSORS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">OMIM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Proposed Function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Pleiotropism (Different Diseases With Which They Have Been Associated) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL23R</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1p31.3 (PSORS7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607562</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes the IL-23 receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, Crohn disease, ulcerative colitis, ankylosing spondylitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL12B</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5q33.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">161561</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes the p40 subunit of IL-12 and IL-23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL13</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5q31.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">147683</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes IL-13; near IL-4, IL-5, and the RAD50 complex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis, asthma, atopy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL23A</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12q13.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">605580</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes the p19 subunit of IL-23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TNFAIP3</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6q23.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">191163</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes the A20 protein, which acts through ubiquitin, inhibiting the proinflammatory activation of TNF-α induced NFκB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis, Crohn disease, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, celiac disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TNIP1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5q33.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607714</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes the ABIN-1 protein, which reduces the proinflammatory activation of TNF-α-induced NFκB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TRAF3IP2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6q21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607043</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes a protein that disrupts IL-17 signaling and interacts with different members of the family of Rel/NF-κB transcription factors. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">ZNF313/RNF114</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20q13 (PSORS12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">612451</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes a ubiquitin ligase that is expressed in the skin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">ADAM33</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20p13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607114</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Disintegrin and metalloprotease 33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, asthma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PTPN22</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1p13.2 (PSORS7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">600716</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tyrosine phosphatase that participates in the signaling of T lymphocyte receptors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, rheumatoid arthritis, systemic lupus erythematosus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CDKAL1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6p22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">611259</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes protein kinase homologous protein \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, Crohn disease, type 2 diabetes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">KIR2DS1, KIR2DL1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19q13.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">604952, 604936</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encode receptors similar to immunoglobulin that bind to HLA-C and regulate the NK cell response. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">LCE3D/LCE3A LCE3C_LCE3B_del</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1q21 (PSORS4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">612616, 612613</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encode late cornified envelope (LCE) proteins, highly expressed in psoriasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">DEFB4</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8p23.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">602215</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes human β-defensin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL15</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4q31.2-q32.1 (PSORS9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes an interleukin that affects the activation and proliferation of T lymphocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL2, IL21</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4q27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">147680, 605384</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encode interleukins that participate in the proliferation of T lymphocytes, Th17 differentiation, and keratinocyte proliferation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriatic arthritis, rheumatoid arthritis, type 1 diabetes, ulcerative colitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IL28RA</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1p36.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607404</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes the alfa subunit of the IL-23 receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">REL</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2p16.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">164910</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes an oncogene member of the Rel/NFκB transcription factor family \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">IFIH1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2q24.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">606951</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes an interferon-induced helicase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">ERAP1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5q15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">606832</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes an aminopeptidase of the endoplasmic reticulum, participates in the processing of peptides by MHC-I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis in patients positive for <span class="elsevierStyleItalic">HLA-Cw*0602</span>; early onset in Chinese individuals of the Han ethnicity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">NFKBIA</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14q13.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">604495</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes a protein that deactivates NFκB by sequestering it in the cytoplasm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TYK2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19p13.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">176941</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes a protein that participates in the signaling of the type I interferon receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, systemic lupus erythematosus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PTTG1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5q33.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">604147</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Participates in cell proliferation and transformation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CSMD1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8p23.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">608397</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Product participates in complement activation (?) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">GJB2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13q12.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">121011</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Connexin 26 (keratoderma) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">SERPINB8</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18q22.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">601697</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protease 8 inhibitor (regulates multiple functions); increased expression in psoriasis lesions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">ZNF816A</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19q13.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encodes a zinc finger protein (participates in the recognition of RNA and other proteins) of the same class as the <span class="elsevierStyleItalic">ZNF313</span> gene product. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early onset psoriasis in Chinese individuals of the Han ethnicity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">NOS2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17q11.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">163730</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nitric oxide synthetase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis, hypertension, malaria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">FBXL19</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16p11.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">609085</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ubiquitin ligase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PSMA6 (?)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14q13.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">602855</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteasome subunit (regulates inflammation through NFκB) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Psoriasis, psoriatic arthritis, susceptibility to myocardial infarction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">CARD14</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17q25.3-qter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">607211</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Activation of NFκB; participates in apoptosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab521027.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Genes Associated 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 15 | 7 | 22 |
| 2024 October | 144 | 52 | 196 |
| 2024 September | 136 | 47 | 183 |
| 2024 August | 204 | 77 | 281 |
| 2024 July | 165 | 41 | 206 |
| 2024 June | 180 | 75 | 255 |
| 2024 May | 149 | 46 | 195 |
| 2024 April | 151 | 41 | 192 |
| 2024 March | 164 | 33 | 197 |
| 2024 February | 194 | 57 | 251 |
| 2024 January | 175 | 56 | 231 |
| 2023 December | 206 | 47 | 253 |
| 2023 November | 201 | 40 | 241 |
| 2023 October | 231 | 57 | 288 |
| 2023 September | 195 | 46 | 241 |
| 2023 August | 129 | 26 | 155 |
| 2023 July | 165 | 30 | 195 |
| 2023 June | 174 | 32 | 206 |
| 2023 May | 156 | 37 | 193 |
| 2023 April | 145 | 25 | 170 |
| 2023 March | 140 | 32 | 172 |
| 2023 February | 143 | 22 | 165 |
| 2023 January | 82 | 38 | 120 |
| 2022 December | 89 | 50 | 139 |
| 2022 November | 116 | 43 | 159 |
| 2022 October | 80 | 18 | 98 |
| 2022 September | 94 | 43 | 137 |
| 2022 August | 54 | 43 | 97 |
| 2022 July | 64 | 33 | 97 |
| 2022 June | 80 | 43 | 123 |
| 2022 May | 191 | 71 | 262 |
| 2022 April | 162 | 48 | 210 |
| 2022 March | 123 | 62 | 185 |
| 2022 February | 104 | 32 | 136 |
| 2022 January | 115 | 53 | 168 |
| 2021 December | 80 | 47 | 127 |
| 2021 November | 90 | 64 | 154 |
| 2021 October | 75 | 58 | 133 |
| 2021 September | 60 | 50 | 110 |
| 2021 August | 45 | 47 | 92 |
| 2021 July | 67 | 48 | 115 |
| 2021 June | 85 | 56 | 141 |
| 2021 May | 99 | 39 | 138 |
| 2021 April | 161 | 75 | 236 |
| 2021 March | 145 | 37 | 182 |
| 2021 February | 91 | 34 | 125 |
| 2021 January | 61 | 28 | 89 |
| 2020 December | 90 | 30 | 120 |
| 2020 November | 77 | 39 | 116 |
| 2020 October | 67 | 42 | 109 |
| 2020 September | 88 | 44 | 132 |
| 2020 August | 68 | 22 | 90 |
| 2020 July | 70 | 23 | 93 |
| 2020 June | 65 | 32 | 97 |
| 2020 May | 60 | 47 | 107 |
| 2020 April | 63 | 19 | 82 |
| 2020 March | 44 | 36 | 80 |
| 2020 February | 0 | 12 | 12 |
| 2020 January | 4 | 10 | 14 |
| 2019 December | 8 | 12 | 20 |
| 2019 November | 4 | 3 | 7 |
| 2019 October | 0 | 3 | 3 |
| 2019 September | 4 | 6 | 10 |
| 2019 August | 4 | 10 | 14 |
| 2019 July | 6 | 22 | 28 |
| 2019 June | 4 | 27 | 31 |
| 2019 May | 3 | 14 | 17 |
| 2019 April | 0 | 25 | 25 |
| 2019 March | 0 | 10 | 10 |
| 2019 February | 2 | 5 | 7 |
| 2019 January | 0 | 3 | 3 |
| 2018 December | 3 | 5 | 8 |
| 2018 November | 3 | 3 | 6 |
| 2018 October | 2 | 1 | 3 |
| 2018 September | 3 | 2 | 5 |
| 2018 August | 0 | 4 | 4 |
| 2018 July | 0 | 5 | 5 |
| 2018 June | 0 | 3 | 3 |
| 2018 May | 0 | 22 | 22 |
| 2018 April | 0 | 18 | 18 |
| 2018 March | 6 | 11 | 17 |
| 2018 February | 129 | 19 | 148 |
| 2018 January | 185 | 30 | 215 |
| 2017 December | 146 | 37 | 183 |
| 2017 November | 210 | 22 | 232 |
| 2017 October | 165 | 24 | 189 |
| 2017 September | 147 | 41 | 188 |
| 2017 August | 89 | 27 | 116 |
| 2017 July | 106 | 18 | 124 |
| 2017 June | 125 | 34 | 159 |
| 2017 May | 76 | 37 | 113 |
| 2017 April | 64 | 25 | 89 |
| 2017 March | 56 | 30 | 86 |
| 2017 February | 44 | 22 | 66 |
| 2017 January | 89 | 19 | 108 |
| 2016 December | 90 | 22 | 112 |
| 2016 November | 169 | 18 | 187 |
| 2016 October | 133 | 52 | 185 |
| 2016 September | 200 | 26 | 226 |
| 2016 August | 229 | 31 | 260 |
| 2016 July | 82 | 19 | 101 |
| 2016 June | 10 | 16 | 26 |
| 2016 May | 12 | 4 | 16 |
| 2016 April | 9 | 15 | 24 |
| 2016 March | 8 | 7 | 15 |
| 2016 February | 10 | 6 | 16 |
| 2016 January | 16 | 17 | 33 |
| 2015 December | 9 | 5 | 14 |
| 2015 November | 14 | 6 | 20 |
| 2015 October | 6 | 15 | 21 |
| 2015 September | 7 | 17 | 24 |
| 2015 August | 10 | 15 | 25 |
| 2015 July | 147 | 16 | 163 |
| 2015 June | 106 | 27 | 133 |
| 2015 May | 96 | 16 | 112 |
| 2015 April | 96 | 20 | 116 |
| 2015 March | 207 | 20 | 227 |
| 2015 February | 118 | 13 | 131 |
| 2015 January | 72 | 18 | 90 |
| 2014 December | 52 | 13 | 65 |
| 2014 November | 23 | 10 | 33 |
| 2014 October | 20 | 8 | 28 |
| 2014 September | 9 | 8 | 17 |
| 2014 August | 8 | 13 | 21 |
| 2014 July | 7 | 14 | 21 |
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