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Genetic Variations in Cytokines and Cytokine Receptors Associated with Psoriasis Found by Genome-Wide Association

      Genetic variants have long been suspected to be important in psoriasis. Recent work has suggested that HLA-Cw6 on chromosome 6 is the risk variant in the PSORS1 [MIM 177900] susceptibility locus that confers the greatest risk for early onset of psoriasis. Although numerous minor susceptibility loci have been identified by linkage analysis, few biologically relevant candidates have been discovered within these intervals. Recent large-scale genome-wide association studies have yielded new candidates in genes encoding cytokines with functional relevance to psoriasis. Polymorphisms within the genes encoding the IL-12 p40 subunit, IL12B, and one of the IL-23 receptor subunits, IL23R, have been replicated in US and European populations and overlap with risk of Crohn's disease. Polymorphisms within the gene encoding IL-13, a Th2 cytokine, also confer risk for psoriasis. Variants of the gene IL15 encoding IL-15 have been identified that associate with psoriasis in a Chinese population. These discoveries pose the challenge of elucidating the role of common genetic variants in susceptibility to and manifestations of psoriasis.

      Abbreviations

      GWAS
      genome-wide association study
      IBD
      inflammatory bowel disease
      OR
      odds ratio
      SNP
      single-nucleotide polymorphism
      TNF-α
      tumor-necrosis factor-α

      Psoriasis is a Complex Polygenic Disorder

      Psoriasis is a chronic inflammatory disorder that affects 0.6–4.8% of the population worldwide (
      • Naldi L.
      Epidemiology of psoriasis.
      ). Psoriasis has long been considered a disorder with a genetic basis, supported by familial clustering of the disease (
      • Lomholt G.
      Environment and genetics in psoriasis.
      ), increased concordance among monozygotic twins (
      • Brandrup F.
      • Holm N.
      • Grunnet N.
      • Henningsen K.
      • Hansen H.E.
      Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution.
      ) and the repeatedly confirmed association with HLA-Cw6 (
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • Hiremagalore R.
      • Chia N.V.
      • Jenisch S.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ). However, only 60–65% of individuals with psoriasis carry this risk variant, and 15% of individuals without psoriasis carry HLA-Cw6 (
      • Gudjonsson J.E.
      • Karason A.
      • Runarsdottir E.H.
      • Antonsdottir A.A.
      • Hauksson V.B.
      • Jonsson H.H.
      • et al.
      Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients-an analysis of 1019 HLA-C- and HLA-B-typed patients.
      ), lending support to the widely held belief that other common genetic variants contribute to psoriasis susceptibility. In the last decade, numerous genome-wide scans using linkage analysis on multiply affected families, have elucidated eight other replicated susceptibility loci (PSORS2–9) as reviewed by
      • Capon F.
      • Trembath R.C.
      • Barker J.N.
      An update on the genetics of psoriasis.
      . Follow-up sequencing and fine mapping within these susceptibility loci have, to date, yielded few candidate genes with biologic relevance to psoriasis pathophysiology.

      A New Era Of Genome-wide Association

      Genome-wide studies were initially performed using linkage analysis, which relies on the concept that a marker allele near a disease gene is coinherited with that disease gene within a family unless a recombination event has occurred. Marker alleles are then traced in families that have affected and unaffected individuals. With the better understanding of genomic variation of the human genome provided by the
      • International HapMap Consortium
      A haplotype map of the human genome.
      , genome-wide studies can now be performed by association rather than linkage. Association analyses compare the frequencies of the alleles of single-nucleotide polymorphisms (SNPs) between cases and controls. With the advances in high-throughput technologies, sophisticated statistical techniques, and availability of large collections of well-phenotyped patients, large genome-wide association studies (GWAS) can compare the frequencies of hundreds of thousands of SNPs in cases and controls. GWAS have, to date, been successfully used to find risk variants in large cohorts of patients with diabetes, Crohn's disease (
      • Wellcome Trust Case Control Consortium
      Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
      ), and many other disorders with complex inheritance. In the past 2 years, genome-wide case–control studies (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ) and two confirmation analyses (
      • Smith R.L.
      • Warren R.B.
      • Eyre S.
      • Ho P.
      • Ke X.
      • Young H.S.
      • et al.
      Polymorphisms in the IL-12beta and IL-23R genes are associated with psoriasis of early onset in a UK cohort.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ) of psoriasis populations have yielded two candidate loci at IL12B and IL23R. These candidates offer the promise of clinical relevance as their gene products have very recently been considered to have key roles in psoriasis pathophysiology. In addition, other cytokine genes, IL13 and IL15, have been identified as harboring variants that associate with psoriasis. What follows is a review of the recently discovered risk variants in genes encoding cytokines or their receptors and their potential relevance to the pathogenesis of psoriasis.

      Il12b Variants And Psoriasis Risk

      The first large-scale genome-wide case–control association study of psoriasis that yielded an association between psoriasis and cytokines and cytokine receptors relevant to the pathophysiology of psoriasis was reported by
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      . This study was carried out by genotyping 467 well-characterized psoriasis patient from our registry (the Utah Psoriasis Initiative) and 500 controls for 25,215 gene-centric SNPs using a disease-phenotype pooling strategy, a method that essentially screens for associated polymorphisms while conserving DNA. Polymorphisms that associated with psoriasis were evaluated in a second sample set, and those that maintained their significance were then individually genotyped.
      The screening phase of this study revealed a highly significant association of rs3212227 (1188A>C) with psoriasis. The presence of the common (A) allele confers risk of psoriasis with an odds ratio (OR) of 1.59 in the discovery cohort (confidence interval 1.24–2.04, allelic P-value of 1.89 × 10−4) and an OR of 1.81 in the replication cohort (confidence interval 1.42–2.28) (Table 1). This polymorphism, located in the 3′-untranslated region of IL12B, was first described in 2000, but early studies did not detect significant association in patient cohorts of rheumatoid arthritis, multiple sclerosis, or large granular lymphocyte leukemia with or without arthritis (
      • Hall M.A.
      • McGlinn E.
      • Coakley G.
      • Fisher S.A.
      • Boki K.
      • Middleton D.
      • et al.
      Genetic polymorphism of IL-12 p40 gene in immune-mediated disease.
      ). In 2002, a Japanese group reported an increased frequency of the common (A) allele of rs3212227 in psoriasis patients but replication in an independent sample was never performed (
      • Tsunemi Y.
      • Saeki H.
      • Nakamura K.
      • Sekiya T.
      • Hirai K.
      • Fujita H.
      • et al.
      Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.
      ).
      Table 1Summary of genotype frequencies, minor allele frequencies, and odds ratios for IL12B SNP rs3212227
      Genotype frequencyMinor allele frequency
      GenotypePatientsControlsPatientsControlsOdds ratio (for common allele conferring risk) (confidence interval)
      CargillAA0.7360.630
      Discovery
      Cargill et al. (2007).
      AC0.2420.3220.1430.2091.59 (1.24–2.04)
      CC0.0210.047
      CargillAA0.7500.603
      Replication
      Cargill et al. (2007).
      AC0.2260.3480.1370.2231.81 (1.42–2.28)
      CC0.0240.049
      Smith UK
      Smith et al. (2007).
      AA0.7180.647
      AC0.2560.3160.1540.1941.33 (1.11–1.57)
      CC0.0260.036
      Nair US
      Nair et al. (2008).
      AA0.7340.594
      AC0.2440.3460.1450.2211.67 (1.45–1.92)
      CC0.0230.044
      Nair Kiel
      Nair et al. (2008).
      AA0.7300.651
      AC0.2540.3160.1440.1911.41 (1.11–1.50)
      CC0.0170.033
      Capon UKAANANA
      Discovery
      Capon et al. (2007).
      ACNANA0.1500.1801.24 (0.99–1.56)
      CCNANA
      Capon UKAANANA
      Replication
      Capon et al. (2007).
      ACNANA0.1600.2001.31 (1.11–1.55)
      CCNANA
      NA, not applicable.
      1
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      .
      2
      • Smith R.L.
      • Warren R.B.
      • Eyre S.
      • Ho P.
      • Ke X.
      • Young H.S.
      • et al.
      Polymorphisms in the IL-12beta and IL-23R genes are associated with psoriasis of early onset in a UK cohort.
      .
      3
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      .
      4
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      .
      Further sequencing and tagSNP analysis of IL12B also yielded a risk SNP ∼60kb upstream of IL12B, rs6887695 (G>C). Again, the common (G) allele conferred risk in the discovery and two replication cohorts. When considered together, the two IL12B risk SNPs (A-G) form a psoriasis-associated haplotype; individuals homozygous for the risk alleles at both SNPs have a combined OR of 1.40 (Pcombined=8.11 × 10−9) for having psoriasis.
      Since publication of the Cargill paper, three other studies have confirmed the association of IL12B SNPs with psoriasis. Risk alleles of rs3212227 and rs6887695 were both shown to confer risk for psoriasis in a UK data set of early onset psoriasis (
      • Smith R.L.
      • Warren R.B.
      • Eyre S.
      • Ho P.
      • Ke X.
      • Young H.S.
      • et al.
      Polymorphisms in the IL-12beta and IL-23R genes are associated with psoriasis of early onset in a UK cohort.
      ) and in a case–control and family based study performed with US and German patients (
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ). Another study which confirmed association with rs3212227 also identified an additional SNP upstream of IL12B, rs10045431, that was not seen in the Cargill study (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ). In all three studies, the common allele is more frequent in individuals with psoriasis (the minor allele is protective). A summary of the genotype and allele frequencies for rs3212227 (with ORs performed in the context of the common allele conferring “risk”) from these studies is presented in Table 1, which illustrates a modest, yet consistent, effect of this common variant.

      Il23r Variants And Psoriasis Risk

      The discovery of the association of IL12B with psoriasis prompted a thorough search of other risk variants within the IL-12/23 receptor–ligand pathway that associate with psoriasis. This led to the discovery of and report by Cargill et al. of two psoriasis-associated polymorphisms within the gene encoding one subunit of the IL-23 receptor, IL23R. Genotyping and haplotype analysis of SNPs within IL23R yielded two additional SNPs, rs7530511 and rs11209026 that also conferred risk of psoriasis. Of note, the rs11209026 polymorphism is a nonsynonymous SNP that results in an Arg to Gln substitution (Arg381Gln, or Q381R) that had recently been found to associate risk of Crohn's disease (
      • Duerr R.H.
      • Taylor K.D.
      • Brant S.R.
      • Rioux J.D.
      • Silverberg M.S.
      • Daly M.J.
      • et al.
      A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
      ). Both rs7530511 and rs11209026 have been replicated in the aforementioned UK (
      • Smith R.L.
      • Warren R.B.
      • Eyre S.
      • Ho P.
      • Ke X.
      • Young H.S.
      • et al.
      Polymorphisms in the IL-12beta and IL-23R genes are associated with psoriasis of early onset in a UK cohort.
      ) and US and German populations (
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ) and rs11209026 was also significant in the Capon study. A summary of the genotype and allele frequencies for rs11209026 (with ORs performed in the context of the minor allele conferring protection) is presented in Table 2, which again demonstrates a consistently modest effect.
      Table 2Summary of genotype frequencies, minor allele frequencies, and odds ratios for IL23R SNP rs11209026
      Genotype frequencyMinor allele frequency
      Study populationGenotypePatientsControlsPatientsControlsOdds ratio (for minor allele conferring protection) (confidence interval)
      CargillGGNANA
      Discovery
      Cargill et al. (2007).
      GANANA0.0440.0600.73 (0.406–1.299)
      AANANA
      CargillGGNANA
      Replication
      Cargill et al. (2007).
      GANANA0.0510.0770.64 (0.360–1.077)
      AANANA
      Smith UK
      Smith et al. (2007).
      GG0.9260.883
      GA0.0740.1170.0370.0600.62 (0.446–0.848)
      AA0.0000.000
      Nair US
      Nair et al. (2008).
      GG0.8940.867
      GA0.1030.1290.0530.0660.78 (0.573–1.070)
      AA0.0030.004
      Nair Kiel
      Nair et al. (2008).
      GG0.9140.856
      GA0.0860.1370.0430.0720.56 (0.318–0.986)
      AA0.0000.006
      Capon UKGGNANA
      Discovery
      Capon et al. (2007).
      GANANA0.0220.0720.29 (0.158–0.545)
      AANANA
      Capon UKGGNANA
      Replication
      Capon et al. (2007).
      GANANA0.0450.0690.63 (0.430–0.925)
      AANANA
      NA, not applicable.
      1
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      .
      2
      • Smith R.L.
      • Warren R.B.
      • Eyre S.
      • Ho P.
      • Ke X.
      • Young H.S.
      • et al.
      Polymorphisms in the IL-12beta and IL-23R genes are associated with psoriasis of early onset in a UK cohort.
      .
      3
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      .
      4
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      .

      Role Of Il-12 And Il-23 In Psoriasis

      In recent years the roles of cytokines IL-12 and IL-23 in psoriasis have become increasingly more clear (
      • Fitch E.
      • Harper E.
      • Skorcheva I.
      • Kurtz S.E.
      • Blauvelt A.
      Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines.
      ). IL-23 and IL-12 are heterodimeric members of the IL-12 cytokine family. They are structurally related in that they share the p40 subunit; IL-12 is formed by the p40 and p35 subunits; IL-23 is formed by the p19 and p40 subunits. IL-12 is known to promote the differentiation of naïve T cells (Th0) into Th1 lymphocytes, which in turn produce IFN-γ and IL-2. Until recently the “Th1” paradigm was considered central to the development of psoriasis. However, mounting evidence suggests that IL-23 may have a more critical role than IL-12 in the development of psoriasis. Both p40 and p19 mRNA levels are increased in lesional psoriatic skin, whereas p35 is not (
      • Lee E.
      • Trepicchio W.L.
      • Oestreicher J.L.
      • Pittman D.
      • Wang F.
      • Chamian F.
      • et al.
      Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris.
      ). In the presence of IL-6 and transforming growth factor-β, Th0 cells can differentiate into a population of mature T cells distinct from Th1 and Th2, known as Th17 cells. Th17 cells uniquely express the IL-23 receptor, made up of two subunits, IL23R and IL12Rβ1. In the presence of IL-23, Th17 cells produce Th17 cytokines, including IL-17A, IL-17F, IL-6, tumor-necrosis factor (TNF)-α, and IL-22, which drive downstream events that sustain psoriatic plaques. Recent data also suggest that etanercept, a TNF-α, receptor–Ig fusion protein, may inhibit Th17 cytokine production by dendritic cells within the first 2 weeks of therapy, whereas Th1-mediated IFN-γ production diminishes much later, supporting a more upstream role of the Th17 cytokines (
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • Suarez Farinas M.
      • Fuentes-Duculan J.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      ). Last, neutralization of p40 with a human mAb leads to marked clinical improvement of psoriasis plaques, further implicating IL-23 and IL-12 as having an important role in psoriasis (
      • Kauffman C.L.
      • Aria N.
      • Toichi E.
      • McCormick T.S.
      • Cooper K.D.
      • Gottlieb A.B.
      • et al.
      A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis.
      ;
      • Krueger G.G.
      • Langley R.G.
      • Leonardi C.
      • Yeilding N.
      • Guzzo C.
      • Wang Y.
      • et al.
      A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis.
      ). To date, the risk variants in IL12B and IL23R have not been directly linked to the expression of IL-12, IL-23, or other key cytokines playing a role in psoriasis. Figure 1 summarizes the chromosomal location of the risk SNPs at IL12B and IL23R, the subunits that may be affected by these variants, and the Th1 and Th17 cytokines that could be modulated by altered expression of IL-12 or IL-23.
      Figure thumbnail gr1
      Figure 1IL12B and IL23R SNPs. The IL12B SNPs that associate with psoriasis include rs3212227, which resides within the 3′-UTR region of IL12B, and rs6887695, which is ∼60kb upstream of IL12B, on chromosome 5q33. The IL23R SNPs that associate with psoriasis include rs11209026 and rs7530511 on chromosome 1p31.3. IL12B encodes p40, the subunit shared by both IL-12 and IL-23. IL23R encodes one of the two IL-23 receptor subunits. When bound to its cell-surface receptors, IL-12 promotes the differentiation of naïve Th0 cells into Th1 cells, which in turn produce IFNγ and IL-2. In the setting of IL-6 and TGF-β, IL-23 promotes the differentiation of naïve Th0 cells into Th17 cells, which secrete IL-17A, IL-17F, IL-6, TNF-α, and IL-22. The role of the IL12B and IL23R polymorphisms in the expression of IL-12, the IL-23 receptor, and their impact on psoriasis pathophysiology remains unknown.
      (adapted courtesy of Centocor, 2008)

      Il23r Variants And Inflammatory Bowel Disease

      Polymorphisms in IL23R have also been found to associate with risk of inflammatory bowel disease (IBD) and have been replicated in multiple studies. The same SNP that associates with psoriasis, rs11209026, was reported initially in a Crohn's disease case–control study (
      • Duerr R.H.
      • Taylor K.D.
      • Brant S.R.
      • Rioux J.D.
      • Silverberg M.S.
      • Daly M.J.
      • et al.
      A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
      ). Interestingly, this study did not identify the association of Crohn's disease with the IL12B risk variants. The rs11209026 polymorphism and others in IL23R have subsequently been seen in the
      • Wellcome Trust Case Control Consortium
      Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
      GWAS of 14,000 cases and 3,000 controls, and numerous other GWAS of adult Crohn's disease (
      • Libioulle C.
      • Louis E.
      • Hansoul S.
      • Sandor C.
      • Farnir F.
      • Franchimont D.
      • et al.
      Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4.
      ;
      • Parkes M.
      • Barrett J.C.
      • Prescott N.J.
      • Tremelling M.
      • Anderson C.A.
      • Fisher S.A.
      • et al.
      Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.
      ;
      • Raelson J.V.
      • Little R.D.
      • Ruether A.
      • Fournier H.
      • Paquin B.
      • Van Eerdewegh P.
      • et al.
      Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.
      ;
      • Rioux J.D.
      • Xavier R.J.
      • Taylor K.D.
      • Silverberg M.S.
      • Goyette P.
      • Huett A.
      • et al.
      Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.
      ), UC (
      • Buning C.
      • Schmidt H.H.
      • Molnar T.
      • De Jong D.J.
      • Fiedler T.
      • Buhner S.
      • et al.
      Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn's disease but also ulcerative colitis.
      ), and pediatric IBD (
      • Baldassano R.N.
      • Bradfield J.P.
      • Monos D.S.
      • Kim C.E.
      • Glessner J.T.
      • Casalunovo T.
      • et al.
      Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn's disease.
      ;
      • Van Limbergen J.
      • Russell R.K.
      • Nimmo E.R.
      • Drummond H.E.
      • Smith L.
      • Davies G.
      • et al.
      IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland.
      ).
      Like psoriasis, IBD is considered an immune-mediated multifactorial and polygenic disorder. These two conditions frequently overlap. Patients with Crohn's disease have a fivefold risk of developing psoriasis (
      • Lee F.I.
      • Bellary S.V.
      • Francis C.
      Increased occurrence of psoriasis in patients with Crohn's disease and their relatives.
      ) and anti-TNF-α therapies have efficacy in both disorders. Crohn's disease was considered primarily a Th1-mediated disorder until the Th17 pathway emerged, and IL-23, not IL-12, was shown to mediate colitis following intestinal bacterial infection in a mouse model (
      • Hue S.
      • Ahern P.
      • Buonocore S.
      • Kullberg M.C.
      • Cua D.J.
      • McKenzie B.S.
      • et al.
      Interleukin-23 drives innate and T cell-mediated intestinal inflammation.
      ;
      • Uhlig H.H.
      • McKenzie B.S.
      • Hue S.
      • Thompson C.
      • Joyce-Shaikh B.
      • Stepankova R.
      • et al.
      Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology.
      ). Furthermore, a mAb to IL-23p19 has been shown to treat and prevent chronic colitis in a mouse model of IBD (
      • Elson C.O.
      • Cong Y.
      • Weaver C.T.
      • Schoeb T.R.
      • McClanahan T.K.
      • Fick R.B.
      • et al.
      Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice.
      ). Although risk variants within IL23R have an unknown impact on the causation of IBD, a recent study has demonstrated that carriers of the IL23R risk variants have significantly higher serum levels of the Th17 cytokine, IL-22, and greater disease activity scores than the IL23R protective variant carriers (
      • Schmechel S.
      • Konrad A.
      • Diegelmann J.
      • Glas J.
      • Wetzke M.
      • Paschos E.
      • et al.
      Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status.
      ). Thus, more than just circumstantial evidence is emerging to link genetic variation to pathogenesis.

      Il13 And Psoriasis Risk

      Another gene of interest that appeared in the preliminary results of the Cargill genome-wide scan was IL13, the gene that codes for IL-13 that resides within the chromosome 5q31 cytokine cluster. IL-13, like IL-4 and IL-10, is secreted by Th2 cells, propagating the allergic inflammatory response seen in asthma, allergy, helminthic responses, and atopic dermatitis. Given its immunoregulatory role, the same multitiered approach used to identify IL12B and IL23R was used to identify association of psoriasis with three SNPs in IL13: rs1800925, rs20541, and rs848 (
      • Chang M.
      • Li Y.
      • Yan C.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Garcia V.E.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ). Like the IL12B and IL23R SNPs, the common alleles confer a modest degree of risk, with the risk haplotype CCG conferring the most risk with a combined OR of 1.27 (Pcombined=1.88 × 10−4).
      The role of IL-13 in psoriasis is yet to be elucidated. IL-13 and the closely related cytokine, IL-4, bind to and send signals through receptors composed of combinations of four receptor subunits, IL-4Rα1, IL-13Rα1, IL-13Rα2, and a common γ chain. Although IL-13 and IL-4 could not be detected in the skin of psoriasis or healthy controls by RT–PCR or immunohistochemical techniques in two different studies (
      • Van der Ploeg I.
      • Jeddi Tehrani M.
      • Matuseviciene G.
      • Wahlgren C.F.
      • Fransson J.
      • Scheynius A.
      IL-13 over-expression in skin is not confined to IgE-mediated skin inflammation.
      ;
      • Cancino-Diaz J.C.
      • Reyes-Maldonado E.
      • Banuelos-Panuco C.A.
      • Jimenez-Zamudio L.
      • Garcia-Latorre E.
      • Leon-Dorantes G.
      • et al.
      Interleukin-13 receptor in psoriatic keratinocytes: overexpression of the mRNA and underexpression of the protein.
      ), both IL-13Rα1 and IL-4Rα1 mRNA have been shown to be overexpressed in lesional and nonlesional skin (
      • Cancino-Diaz J.C.
      • Reyes-Maldonado E.
      • Banuelos-Panuco C.A.
      • Jimenez-Zamudio L.
      • Garcia-Latorre E.
      • Leon-Dorantes G.
      • et al.
      Interleukin-13 receptor in psoriatic keratinocytes: overexpression of the mRNA and underexpression of the protein.
      ). When added to primary keratinocyte cultures, IL-13 has been shown to increase IL-6 (
      • Derocq J.M.
      • Segui M.
      • Poinot-Chazel C.
      • Minty A.
      • Caput D.
      • Ferrara P.
      • et al.
      Interleukin-13 stimulates interleukin-6 production by human keratinocytes. Similarity with interleukin-4.
      ;
      • Wongpiyabovorn J.
      • Suto H.
      • Ushio H.
      • Izuhara K.
      • Mitsuishi K.
      • Ikeda S.
      • et al.
      Up-regulation of interleukin-13 receptor alpha1 on human keratinocytes in the skin of psoriasis and atopic dermatitis.
      ), an important cytokine in the early development of Th17 cells. Although still speculative at this time, IL-13 be important in the dysregulation of the innate and adaptive immune response that leads to psoriasis.

      Il15 And Psoriasis Risk

      IL-15 is also a cytokine of interest in both the pathogenesis and genetic susceptibility of psoriasis, as recently reviewed (
      • Elder J.T.
      IL-15 and psoriasis: another genetic link to Th17?.
      ). IL-15 and its receptor IL-15Rα are expressed by keratinocytes (
      • McInnes I.B.
      • Gracie J.A.
      Interleukin-15: a new cytokine target for the treatment of inflammatory diseases.
      ), and IL-15 is known to be overexpressed in lesional psoriatic epidermis (
      • Ruckert R.
      • Asadullah K.
      • Seifert M.
      • Budagian V.M.
      • Arnold R.
      • Trombotto C.
      • et al.
      Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis?.
      ). IL-15 upregulates many proinflammatory cytokines, including TNF-α, IFN-γ, macrophage inflammatory protein-1α and -1β, IL-1β, and IL-10 (
      • Fehniger T.A.
      • Caligiuri M.A.
      Interleukin 15: biology and relevance to human disease.
      ), and activates human neutrophils (
      • Girard D.
      • Paquet M.E.
      • Paquin R.
      • Beaulieu A.D.
      Differential effects of interleukin-15 (IL-15) and IL-2 on human neutrophils: modulation of phagocytosis, cytoskeleton rearrangement, gene expression, and apoptosis by IL-15.
      ). IL-15 also stimulates production of IL-17 by T lymphocytes (
      • Hoeve M.A.
      • Savage N.D.
      • de Boer T.
      • Langenberg D.M.
      • de Waal Malefyt R.
      • Ottenhoff T.H.
      • et al.
      Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells.
      ). Furthermore, antibodies targeting IL-15 bound to its receptor led to reduction of psoriasiform lesions on a xenograft mouse model (
      • Villadsen L.S.
      • Schuurman J.
      • Beurskens F.
      • Dam T.N.
      • Dagnaes-Hansen F.
      • Skov L.
      • et al.
      Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model.
      ).
      IL15 resides on chromosome 4q28–31, within the PSORS9 psoriasis susceptibility locus found originally by linkage analysis (
      • Zhang X.J.
      • He P.P.
      • Wang Z.X.
      • Zhang J.
      • Li Y.B.
      • Wang H.Y.
      • et al.
      Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans.
      ;
      • Sagoo G.S.
      • Tazi-Ahnini R.
      • Barker J.W.
      • Elder J.T.
      • Nair R.P.
      • Samuelsson L.
      • et al.
      Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population.
      ). A recent case–control analysis of SNPs in the region identified a highly significant association of four IL15 SNPs, the most significant being g.96516A → T in the 3′-untranslated region region, with an ORgenotypic of 1.86 (P=4 × 10−7) (
      • Zhang X.J.
      • Yan K.L.
      • Wang Z.M.
      • Yang S.
      • Zhang G.L.
      • Fan X.
      • et al.
      Polymorphisms in interleukin-15 gene on chromosome 4q31.2 are associated with psoriasis vulgaris in Chinese population.
      ). Further investigation of transcriptional activity using a luciferase reporter assay suggested that the risk haplotypes were associated with higher expression activity, lending support to a functional role of these risk variants.

      Multilocus Models Of Genetic Susceptibility

      A great deal of interest now lies in determining if these risk variants interact or synergize to increase psoriasis susceptibility.
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      were unable to detect evidence of epistasis between HLA-Cw6 and the risk variants in IL12B and IL23R in a two-locus logistic regression model, but asserted that the term “epistasis” is not well defined biologically or statistically. We also have demonstrated lack of any additive or synergistic effect in logistic regression and case–control analyses (Tables 3, 4 and 5). Table 3 shows the case–control analysis with HLA-Cw*0602 in our population (OR 4.0) (Table 3). The logistic regression analysis, shown in Table 4, reveals a higher OR for individuals carrying both Cw*0602 and the IL12B AA (risk) genotype (OR=6.17), but did not reveal any evidence of interaction (χ2=1.0, P=0.32 when compared to those carrying neither risk allele), suggesting that the effects of HLA-Cw6 and IL12B are independent. Analysis of HLA-Cw*0602+ cases and controls show that the additional presence of the IL12B risk genotype does not significantly increase risk of psoriasis (OR=1.23, P=0.49) (Table 5). However, in HLA-Cw*0602- cases and controls, presence of the minor allele does is associated with reduced risk, suggesting that the minor allele of rs3212227 may confer additional protection. We conclude that presence of HLA-Cw*0602 still confers the highest risk of psoriasis, and the effects of the IL12, IL23R, and IL13 polymorphisms are quite modest as would be expected for a common disease variant (
      • Bodmer W.
      • Bonilla C.
      Common and rare variants in multifactorial susceptibility to common diseases.
      ). To date, there are no statistical or biological models that suggest epistasis, but analyses of risk between the highest- and lowest-risk genotype classes in both the Chang and Nair studies suggest that obtaining a multilocus genotype may have prognostic utility in the future (
      • Chang M.
      • Li Y.
      • Yan C.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Garcia V.E.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ). Discovering epistatic interactions in large data sets will present a significant challenge, given the computational complexity of analyzing all possible combinations of SNPs, and some authors have suggested that examining protein–protein interaction will facilitate gene interaction discoveries (
      • Pattin K.A.
      • Moore J.H.
      Exploiting the proteome to improve the genome-wide genetic analysis of epistasis in common human diseases.
      ).
      Table 3Psoriasis cases and controls with (+) or without (-) Cw*0602
      Cw*0602+Cw*0602-OR (CI)
      Cases2092884.01 (2.93–5.48)
      Controls69381
      Table 4Logistic regression in psoriasis cases and controls for presence (+) or absence (-) of HLA-Cw*0602 and IL12B rs3212227 risk genotype AA
      Cw*0602rs3212227 AAOR (CI)P-value
      --1.0 (reference)
      -+1.74 (1.25–2.44)0.001
      +-5.01 (2.85–8.82)<0.0001
      ++6.17 (4.01–9.49)<0.0001
      Table 5Cw*0602 in psoriasis cases and controls with HLA-Cw*0602, with or without IL12B rs3212227-risk genotype AA
      Cw*0602 +/rs3212227 AACw*0602 +/rs3212227 AC or CCOR (CI)
      Cases150571.23 (0.68–2.22)
      Controls4722

      Perspective

      The identification of genetic variations in or near genes encoding cytokines and cytokine receptors with functional relevance to psoriasis pathogenesis provides compelling evidence that GWA is a powerful tool in finding common genetic variants. Replication of the risk variants in different populations with very similar ORs also supports the validity of the association. These findings also harmonize with previous assertions by psoriasis genetics researchers that several psoriasis genes exist and are scattered throughout the genome, and that some of these genes may be involved in a variety of other inflammatory or immune-mediated diseases other than psoriasis (
      • Tarlow J.K.
      • Cork M.J.
      • Clay F.E.
      • Schmitt-Egenolf M.
      • Crane A.M.
      • Stierle C.
      • et al.
      Association between interleukin-1 receptor antagonist (IL-1ra) gene polymorphism and early and late-onset psoriasis.
      ;
      • Elder J.T.
      • Nair R.P.
      • Henseler T.
      • Jenisch S.
      • Stuart P.
      • Chia N.
      • et al.
      The genetics of psoriasis 2001: the odyssey continues.
      ). It is quite possible that many more common variants exist and contribute to psoriasis risk. For this reason, collaborative efforts to pool larger cohorts of cases such as Genetics Association Information Network (
      • Manolio T.A.
      • Rodriguez L.L.
      • Brooks L.
      • Abecasis G.
      • Ballinger D.
      • Daly M.
      • et al.
      New models of collaboration in genome-wide association studies: the Genetic Association Information Network.
      ), which will yield genotypes on over 400,000 SNPs in ∼1,400 cases and ∼1,400 controls, are underway. Meta-analyses and replication efforts with additional patient cohorts are expected to yield important new variants with modest relative risk that have been missed in studies with smaller sample sizes.
      Although GWAS have improved our ability to identify new genetic variants that associate with psoriasis, other technologies will be likely be needed to find other important variants missed by GWAS. Although large studies such as Genetics Association Information Network have increasingly dense SNP platforms, GWAS will not be useful in finding individually rare variants that may be associated with much higher risks of disease, with particular relevance to psoriasis in the familial setting. Genome-wide association also does not allow for assessment of genomic copy number, although the latest platforms now include specific copy number variant probes. Copy number variation in the 8p23.1 β-defensin cluster was recently associated with risk of psoriasis, but this locus was not identified on previous GWAS (
      • Hollox E.J.
      • Huffmeier U.
      • Zeeuwen P.L.
      • Palla R.
      • Lascorz J.
      • Rodijk-Olthuis D.
      • et al.
      Psoriasis is associated with increased beta-defensin genomic copy number.
      ).
      Ultimately, it will be necessary to translate the information gained from the study of genetic susceptibility to psoriasis to the pathogenesis of psoriasis. Genome-wide studies will likely provide a large number of candidates that will need to be tested for their functional relevance and for their potential genetic interactions. Studies are needed to link the presence of cytokine polymorphisms with molecular events, such as variations in transcription and translation, in patients with psoriasis and other immune-mediated disorders. It is our hope that risk variants can be linked to disease expression, such as development of psoriatic arthritis or response to therapy, providing useful prognostic information in the clinic.

      ACKNOWLEDGMENTS

      We thank David Goldgar, PhD, for his assistance with statistical analysis of our data and for comments on the paper.

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