Genetic Variations in Cytokines and Cytokine Receptors Associated with Psoriasis Found by Genome-Wide Association
2008; Elsevier BV; Volume: 129; Issue: 4 Linguagem: Inglês
10.1038/jid.2008.308
ISSN1523-1747
AutoresKristina Callis Duffin, Gerald G. Krueger,
Tópico(s)Digestive system and related health
ResumoGenetic 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. 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. genome-wide association study inflammatory bowel disease odds ratio single-nucleotide polymorphism tumor-necrosis factor-α Psoriasis is a chronic inflammatory disorder that affects 0.6–4.8% of the population worldwide (Naldi, 2004Naldi L. Epidemiology of psoriasis.Curr Drug Targets Inflamm Allergy. 2004; 3: 121-128Crossref PubMed Scopus (226) Google Scholar). Psoriasis has long been considered a disorder with a genetic basis, supported by familial clustering of the disease (Lomholt, 1976Lomholt G. Environment and genetics in psoriasis.Ann Clin Res. 1976; 8: 290-297PubMed Google Scholar), increased concordance among monozygotic twins (Brandrup et al., 1982Brandrup F. Holm N. Grunnet N. Henningsen K. Hansen H.E. Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution.Acta Derm Venereol. 1982; 62: 229-236PubMed Google Scholar) and the repeatedly confirmed association with HLA-Cw6 (Nair et al., 2006Nair 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.Am J Hum Genet. 2006; 78: 827-851Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar). However, only 60–65% of individuals with psoriasis carry this risk variant, and 15% of individuals without psoriasis carry HLA-Cw6 (Gudjonsson et al., 2006Gudjonsson 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.J Invest Dermatol. 2006; 126: 740-745Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar), 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 et al., 2004Capon F. Trembath R.C. Barker J.N. An update on the genetics of psoriasis.Dermatol Clin. 2004; 22 (vii): 339-347Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar. Follow-up sequencing and fine mapping within these susceptibility loci have, to date, yielded few candidate genes with biologic relevance to psoriasis pathophysiology. 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, 2005International HapMap Consortium A haplotype map of the human genome.Nature. 2005; 437: 1299-1320Crossref PubMed Scopus (4773) Google Scholar, 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, 2007Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678Crossref PubMed Scopus (7776) Google Scholar), and many other disorders with complex inheritance. In the past 2 years, genome-wide case–control studies (Capon et al., 2007Capon 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.Hum Genet. 2007; 122: 201-206Crossref PubMed Scopus (352) Google Scholar; Cargill et al., 2007Cargill 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.Am J Hum Genet. 2007; 80: 273-390Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar) and two confirmation analyses (Smith et al., 2007Smith 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.J Invest Dermatol. 2007; 128: 1325-1327Crossref PubMed Scopus (67) Google Scholar; Nair et al., 2008Nair 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.J Invest Dermatol. 2008; 128: 1653-1661Crossref PubMed Scopus (234) Google Scholar) 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. 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 et al., 2007Cargill 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.Am J Hum Genet. 2007; 80: 273-390Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar. 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 et al., 2000Hall 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.Genes Immun. 2000; 1: 219-224Crossref PubMed Scopus (136) Google Scholar). 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 et al., 2002Tsunemi 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.J Dermatol Sci. 2002; 30: 161-166Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar).Table 1Summary of genotype frequencies, minor allele frequencies, and odds ratios for IL12B SNP rs3212227Genotype frequencyMinor allele frequencyGenotypePatientsControlsPatientsControlsOdds ratio (for common allele conferring risk) (confidence interval)CargillAA0.7360.630Discovery1Cargill et al. (2007).AC0.2420.3220.1430.2091.59 (1.24–2.04)CC0.0210.047CargillAA0.7500.603Replication1Cargill et al. (2007).AC0.2260.3480.1370.2231.81 (1.42–2.28)CC0.0240.049Smith UK2Smith et al. (2007).AA0.7180.647AC0.2560.3160.1540.1941.33 (1.11–1.57)CC0.0260.036Nair US3Nair et al. (2008).AA0.7340.594AC0.2440.3460.1450.2211.67 (1.45–1.92)CC0.0230.044Nair Kiel3Nair et al. (2008).AA0.7300.651AC0.2540.3160.1440.1911.41 (1.11–1.50)CC0.0170.033Capon UKAANANADiscovery4Capon et al. (2007).ACNANA0.1500.1801.24 (0.99–1.56)CCNANACapon UKAANANAReplication4Capon et al. (2007).ACNANA0.1600.2001.31 (1.11–1.55)CCNANANA, not applicable.1 Cargill et al., 2007Cargill 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.Am J Hum Genet. 2007; 80: 273-390Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar.2 Smith et al., 2007Smith 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.J Invest Dermatol. 2007; 128: 1325-1327Crossref PubMed Scopus (67) Google Scholar.3 Nair et al., 2008Nair 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.J Invest Dermatol. 2008; 128: 1653-1661Crossref PubMed Scopus (234) Google Scholar.4 Capon et al., 2007Capon 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.Hum Genet. 2007; 122: 201-206Crossref PubMed Scopus (352) Google Scholar. Open table in a new tab NA, not applicable. 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 et al., 2007Smith 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.J Invest Dermatol. 2007; 128: 1325-1327Crossref PubMed Scopus (67) Google Scholar) and in a case–control and family based study performed with US and German patients (Nair et al., 2008Nair 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.J Invest Dermatol. 2008; 128: 1653-1661Crossref PubMed Scopus (234) Google Scholar). 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 et al., 2007Capon 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.Hum Genet. 2007; 122: 201-206Crossref PubMed Scopus (352) Google Scholar). 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. 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 et al., 2006Duerr 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.Science. 2006; 314: 1461-1463Crossref PubMed Scopus (2447) Google Scholar). Both rs7530511 and rs11209026 have been replicated in the aforementioned UK (Smith et al., 2007Smith 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.J Invest Dermatol. 2007; 128: 1325-1327Crossref PubMed Scopus (67) Google Scholar) and US and German populations (Nair et al., 2008Nair 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.J Invest Dermatol. 2008; 128: 1653-1661Crossref PubMed Scopus (234) Google Scholar) 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 rs11209026Genotype frequencyMinor allele frequencyStudy populationGenotypePatientsControlsPatientsControlsOdds ratio (for minor allele conferring protection) (confidence interval)CargillGGNANADiscovery1Cargill et al. (2007).GANANA0.0440.0600.73 (0.406–1.299)AANANACargillGGNANAReplication1Cargill et al. (2007).GANANA0.0510.0770.64 (0.360–1.077)AANANASmith UK2Smith et al. (2007).GG0.9260.883GA0.0740.1170.0370.0600.62 (0.446–0.848)AA0.0000.000Nair US3Nair et al. (2008).GG0.8940.867GA0.1030.1290.0530.0660.78 (0.573–1.070)AA0.0030.004Nair Kiel3Nair et al. (2008).GG0.9140.856GA0.0860.1370.0430.0720.56 (0.318–0.986)AA0.0000.006Capon UKGGNANADiscovery4Capon et al. (2007).GANANA0.0220.0720.29 (0.158–0.545)AANANACapon UKGGNANAReplication4Capon et al. (2007).GANANA0.0450.0690.63 (0.430–0.925)AANANANA, not applicable.1 Cargill et al., 2007Cargill 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.Am J Hum Genet. 2007; 80: 273-390Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar.2 Smith et al., 2007Smith 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.J Invest Dermatol. 2007; 128: 1325-1327Crossref PubMed Scopus (67) Google Scholar.3 Nair et al., 2008Nair 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.J Invest Dermatol. 2008; 128: 1653-1661Crossref PubMed Scopus (234) Google Scholar.4 Capon et al., 2007Capon 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.Hum Genet. 2007; 122: 201-206Crossref PubMed Scopus (352) Google Scholar. Open table in a new tab NA, not applicable. In recent years the roles of cytokines IL-12 and IL-23 in psoriasis have become increasingly more clear (Fitch et al., 2007Fitch E. Harper E. Skorcheva I. Kurtz S.E. Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines.Curr Rheumatol Rep. 2007; 9: 461-467Crossref PubMed Scopus (289) Google Scholar). 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 et al., 2004Lee 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.J Exp Med. 2004; 199: 125-130Crossref PubMed Scopus (775) Google Scholar). 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 et al., 2007Zaba 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.J Exp Med. 2007; 204: 3183-3194Crossref PubMed Scopus (542) Google Scholar). 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 et al., 2004Kauffman 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.J Invest Dermatol. 2004; 123: 1037-1044Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar; Krueger et al., 2007Krueger 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.N Engl J Med. 2007; 356: 580-592Crossref PubMed Scopus (702) Google Scholar). 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. 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 et al., 2006Duerr 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.Science. 2006; 314: 1461-1463Crossref PubMed Scopus (2447) Google Scholar). 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, 2007Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678Crossref PubMed Scopus (7776) Google Scholar GWAS of 14,000 cases and 3,000 controls, and numerous other GWAS of adult Crohn's disease (Libioulle et al., 2007Libioulle 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.PLoS Genet. 2007; 3: e58Crossref PubMed Scopus (462) Google Scholar; Parkes et al., 2007Parkes 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.Nat Genet. 2007; 39: 830-832Crossref PubMed Scopus (968) Google Scholar; Raelson et al., 2007Raelson 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.Proc Natl Acad Sci USA. 2007; 104: 14747-14752Crossref PubMed Scopus (181) Google Scholar; Rioux et al., 2007Rioux 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.Nat Genet. 2007; 39: 596-604Crossref PubMed Scopus (1470) Google Scholar), UC (Buning et al., 2007Buning 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.Aliment Pharmacol Ther. 2007; 26: 1025-1033Crossref PubMed Scopus (40) Google Scholar), and pediatric IBD (Baldassano et al., 2007Baldassano 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.Clin Gastroenterol Hepatol. 2007; 5: 972-976Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar; Van Limbergen et al., 2007Van 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.Gut. 2007; 56: 1173-1174Crossref PubMed Scopus (78) Google Scholar). 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 et al., 1990Lee F.I. Bellary S.V. Francis C. Increased occurrence of psoriasis in patients with Crohn's disease and their relatives.Am J Gastroenterol. 1990; 85: 962-963PubMed Google Scholar) 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 et al., 2006Hue 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.J Exp Med. 2006; 203: 2473-2483Crossref PubMed Scopus (680) Google Scholar; Uhlig et al., 2006Uhlig 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.Immunity. 2006; 25: 309-318Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar). Furthermore, a mAb to IL-23p19 has been shown to treat and prevent chronic colitis in a mouse model of IBD (Elson et al., 2007Elson 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.Gastroenterology. 2007; 132: 2359-2370Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). 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 et al., 2008Schmechel 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.Inflamm Bowel Dis. 2008; 14: 204-212Crossref PubMed Scopus (165) Google Scholar). Thus, more than just circumstantial evidence is emerging to link genetic variation to pathogenesis. 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 et al., 2008Chang 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.Genes Immun. 2008; 9: 176-181Crossref PubMed Scopus (59) Google Scholar). 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 et al., 1997Van 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.Clin Exp Immunol. 1997; 109: 526-532Crossref PubMed Scopus (24) Google Scholar; Cancino-Diaz et al., 2002Cancino-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.J Invest Dermatol. 2002; 119: 1114-1120Crossref PubMed Scopus (21) Google Scholar), both IL-13Rα1 and IL-4Rα1 mRNA have been shown to be overexpressed in lesional and nonlesional skin (Cancino-Diaz et al., 2002Cancino-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 u
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