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Genetic Alterations in Psoriasis
JOURNAL CLUB
For the article: http://dx.doi.org/10.1038/sj.jid.5701255 For discussion and answers: http://network.nature.com/group/jidclub
Genetic Alterations in Psoriasis Deborah Zell1, Shasa Hu1 and Robert Kirsner1 Journal of Investigative Dermatology (2008), 128, 1614. doi:10.1038/jid.2008.160
The genetic basis of psoriasis has long been recognized, including the knowledge that family members of patients with psoriasis are at greater risk of developing the disease (Henselers and Christophers, 1995). Several lines of evidence suggest that genes regulating IL-12 and IL-23 may be important in its pathogenesis. Part of the rationale stems from observations indicating that patients with psoriasis and those with Crohn’s disease share common features: patients with Crohn’s disease are five times more likely than the general population to have psoriasis, and both diseases respond to anti–tumor necrosis factor-α therapy (Lee et al., 1990). A recent genomewide association scan identified a highly significant association between Crohn’s disease and a single-nucleotide polymorphism (SNP) in the coding region of the IL23R gene (Duerr et al., 2006), suggesting that this polymorphism might be present in patients with psoriasis. Additional studies from several diverse ethnic populations throughout the world have determined that psoriasis is associated with SNPs in IL-12 and IL-23 or their receptors (Capon et al., 2007; Cargill et al., 2007; Chang et al., 2007; Tsunemi et al., 2002). On the basis of the above information, Nair et al. (2008) studied four candidate SNPs in a large (more than 4,000 persons) cohort of white North American and German subjects with psoriasis and in controls. Two of the SNPs were the IL12B haplotype rs3212227 and rs6887695; the other two were IL23R haplotype rs7530511 and rs11209026. Nair et al. found that both IL12B markers had a highly significant association with psoriasis (odds ratio (OR) 1.62 and 1.49 for rs3212227 and rs6887695, respectively). The IL23R SNPs also demonstrated significant associations in the cases and controls (OR 1.22 and 1.40 for rs7530511 and rs11209026, respectively). These SNPs were not found to have interactions with a known genetic risk factor, HLA-Cw6. Through the following questions, we examine this paper in greater detail. For brief answers, please refer to http:// network.nature.com/group/jidclub. REFERENCES
Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L et al. (2007) Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet 122:201–6 Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–90 Chang YT, Chou CT, Yu CW, Lin MW, Shiao YM, Chen CC et al. (2007) Cytokine gene polymorphisms in Chinese patients with psoriasis. Br J Dermatol 156:899– 905 Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–3 Henselers T, Christophers E (1995). Disease concomitance in psoriasis. J Am Acad Dermatol 32:982–6 Lee FI, Bellary SV, Francis C (1990) Increased occurrence of psoriasis in patients with Crohn’s disease and their relatives [comments]. Am J Gastroenterol 85:962–3 Nair RP, Ruether A, Stuart PE, Jenisch S, Tejasvi T, Hiremagalore R et al. (2008) Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J Invest Dermatol 128: 1653–61 Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H et al. (2002) Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30:161–6
QUESTIONS 1. What is a single-nucleotide polymorphism (SNP)? 2. What data support an association between Crohn’s disease and psoriasis? 3. Why are IL12B and IL23R candidates for study? 4. How was the study performed? 5. What were the major findings of this study? 6. What may be the clinical implications of this study, and how may they change the way we think about the genetics of psoriasis? 7. What future studies might extend these findings? 1
Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
1614 Journal of Investigative Dermatology (2008), Volume 128
© 2008 The Society for Investigative Dermatology
July 2008 Journal Club Article: Genetic Alterations in Psoriasis from Jour...
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Journal of Investigative Dermatology Journal Club
July 2008 Journal Club Article: Genetic Alterations in Psoriasis
Topic Article Polymorphisms of the IL12B and IL23R Genes Are Associated with Psoriasis Rajan P. Nair, Andreas Ruether, Philip E. Stuart, Stefan Jenisch, Trilokraj Tejasvi, Ravi Hiremagalore, Stefan Schreiber, Dieter Kabelitz, Henry W. Lim, John J. Voorhees, Enno Christophers, James T. Elder and Michael Weichenthal Journal of Investigative Dermatology (2008) 128, 1653-61; doi:10.1038/sj.jid.5701255 Genetic Alterations in Psoriasis Deborah Zell 1, Shasa Hu 1 and Robert Kirsner 1 Journal of Investigative Dermatology (2008), 128, 1614. doi:10.1038/jid.2008.160 The genetic basis of psoriasis has long been recognized, including the knowledge that family members of patients with psoriasis are at greater risk of developing the disease (Henselers and Christophers, 1995). Several lines of evidence suggest that genes regulating IL-12 and IL-23 may be important in its pathogenesis. Part of the rationale stems from observations indicating that patients with psoriasis and those with Crohn’s disease share common features: patients with Crohn’s disease are five times more likely than the general population to have psoriasis, and both diseases respond to anti–tumor necrosis factor-α therapy (Lee et al., 1990). A recent genome-wide association scan identified a highly significant association between Crohn’s disease and a single-nucleotide polymorphism (SNP) in the coding region of the IL23R gene (Duerr et al., 2006), suggesting that this polymorphism might be present in patients with psoriasis. Additional studies from several diverse ethnic populations throughout the world have determined that psoriasis is associated with SNPs in IL-12 and IL-23 or their receptors (Capon et al., 2007; Cargill et al., 2007; Chang et al., 2007; Tsunemi et al., 2002). On the basis of the above information, Nair et al. (2008) studied four candidate SNPs in a large (more than 4,000 persons) cohort of white North American and German subjects with psoriasis and in controls. Two of the SNPs were the IL12B haplotype rs3212227 and rs6887695; the other two were IL23R haplotype rs7530511 and rs11209026. Nair et al. found that both IL12B markers had a highly significant association with psoriasis (odds ratio (OR) 1.62 and 1.49 for rs3212227 and rs6887695, respectively). The IL23R SNPs also demonstrated significant associations in the cases and controls (OR 1.22 and 1.40 for rs7530511 and rs11209026, respectively). These SNPs were not found to have interactions with a known genetic risk factor, HLA-Cw6. Through the following questions, we examine this paper in greater detail. QUESTIONS 1. What is a single-nucleotide polymorphism (SNP)? 2. What data support an association between Crohn’s disease and psoriasis? 3. Why are IL12B and IL23R candidates for study? 4. How was the study performed? 5. What were the major findings of this study? 6. What may be the clinical implications of this study, and how may they change the way we think about the genetics of psoriasis? 7. What future studies might extend these findings? ANSWERS 1. A single-nucleotide polymorphism (SNP) occurs when one nucleotide in the genome sequence is substituted for another. SNPs occur relatively frequently and may occur anywhere in the gene sequence. A SNP within an individual’s genome leads to differences in the paired chromosomes in that individual. For a variation to be viewed as a SNP, by definition it must occur in more than 1% of a large population. SNPs are not homogeneous among populations, however, and a SNP allele common in one geographical or ethnic group may be much rarer in another (Yamada, 2008).
8/10/2009 1:42 PM
July 2008 Journal Club Article: Genetic Alterations in Psoriasis from Jour...
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The mere presence of a SNP does not necessarily mean that a disease will result. For instance, a change in a single nucleotide may not result in a change in an amino acid. Owing to degeneracy of the genetic code, multiple-nucleotide triplets may code for the same amino acid, in which case the SNP is termed “synonymous,” or a silent mutation. Although a SNP may occur in a noncoding sequence, this does not imply that the variation will not result in disease, as SNPs in non-protein-coding regions may affect gene splicing, among other activities (Shastry, 2007). 2. Both psoriasis and Crohn’s disease are systemic inflammatory conditions. These diseases share a strong, albeit multifactorial, genetic basis, and both disorders respond well to tumor necrosis-α inhibitors (Najarian and Gottlieb, 2003). Patients with Crohn’s disease are five times more likely to have psoriasis than controls, suggesting a genetic link (Lee et al., 1990). The CARD15 gene has been convincingly associated with Crohn’s disease (Hampe et al., 2001; Hugot, 2006), and in one study it was associated with psoriatic arthritis (Rahman et al., 2003), supporting the notion of a shared genetic predisposition for the two diseases. In this and other studies, whole-genome association studies have identified two non–major histocompatibility complex disease genes (IL12B and IL23R), both of which also confer susceptibility to Crohn’s disease. In a recent case–control study of patients with Crohn’s disease and psoriasis, analysis of 1,256 patients and 2,938 unrelated controls revealed significant associations for loci mapping to chromosomes 1q24, 6p22, and 21q22 (Wolf et al., 2008). Interestingly, CDKAL1, a gene also associated with type 2 diabetes, was mapped to one purportedly involved SNP, rs6908425. These results support evidence for a pleiotropic role for multiple genes that contribute to the pathogenesis of both psoriasis and Crohn’s disease and—potentially—other immune-related diseases. 3. Recent studies have found an association between both IL12B and IL23R and psoriasis. Duerr et al. (2006) performed a genome-wide association scan that identified a highly significant association between a SNP in the IL23R gene (rs11209026) and Crohn’s disease. In addition, Cargill et al. (2007) performed a gene-centric genome-wide association scan in psoriasis, identifying a significant association with SNPs in the IL12B gene (which encodes for the p40-subunit common in both interleukin (IL)-12 and IL-23) and SNP rs1129026 in IL23. During the course of this study, two other discoveries confirmed associations with IL12B in psoriasis (Tsunemi et al., 2002) and IL12B and IL23R in psoriasis (Capon et al., 2007; Chang et al., 2007). 4. The authors performed a genetic epidemiology study. The application of high-quality genetic testing in association with classic epidemiologic methods provides a powerful tool for understanding population genetics. Using tissue from patients with psoriasis from centers in Ann Arbor, Michigan, and Kiel, Germany, or tissue provided by the National Psoriasis Foundation Tissue Bank, a case–control methodology was performed. The case–control sample included 360 cases and 1,097 controls from Kiel, as well as 1,450 cases and 1,425 controls from Ann Arbor. All cases had either plaque or guttate psoriasis, and both cases and controls were of European Caucasian ancestry. In a typical case–control study, risk factors for disease are analyzed to determine whether certain factors are more likely to be seen in cases than in controls. In this study, the risk factor for disease development was each individual’s “exposure” to a specific SNP. For each patient and control, DNA was prepared from peripheral blood mononuclear cells or Epstein–Barr virus–immortalized lymphoblastoid cell lines. SNPs were genotyped by single-base primer extension as implemented in the SnapShot assay protocol or by using the TaqMan allelic discrimination method (Nair et al., 2006). In addition to the four SNPs for the IL12B and IL23R genes, seven SNPs in exons 2 and 3 of the HLA-C gene were also typed, in order to provide unambiguous HLACw6 genotypes even in the absence of phasing (Nair et al., 2006). 5. This study confirmed the findings of other recently published work. In this study, highly significant associations between psoriasis and both IL12B and IL23R were found in a large Caucasian sample. Of the two, IL12B was found to be associated with a higher increased risk (25-fold) than IL23R (16-fold). Further, genetic epidemiology analysis was performed among members of affected families. In the familial analysis, the investigators found positive results for IL12B, but they were unable to confirm the case–control results for IL23R. This lends further support to the relative importance of IL12B. Since other genes have been associated with an increased risk of developing psoriasis, it was important to determine whether the findings were novel or due to interaction with other known genetic risk factors. Specifically, HLA-Cw6 is well known to be associated with psoriasis. However, in this study, no statistical evidence of interaction between IL12B and IL23R and HLA-Cw6 was demonstrated. This finding supports that IL12B and IL23R are associated with psoriasis and independent of HLA-Cw6. 6. In addition to providing a better understanding of the genetics of psoriasis, this paper may eventually prove to have several unexpected implications. Emerging data have implicated IL-12 and IL-23 in the pathogenesis of psoriatic lesions and the involvement of a unique T-cell subset, T-IL-17 (Nickoloff, 2007; Torti and Feldman 2007). This finding may have a genetic basis, and as a consequence may help to explain the epidemiologic association between psoriasis and vascular disease. This work may also explain recent therapeutic advances, particularly the initial success of an anti-IL-12/23 p40 monoclonal antibody therapy for psoriasis (Krueger et al., 2007). Similar to psoriasis, atherosclerosis may be a chronic inflammatory disease of the arterial wall. Disease may result as a consequence of the intricate interplay among several cellular and humoral immunologic factors (Willerson and Ridker, 2004). The presence of psoriasis—and systemic inflammation such as that seen in psoriasis—appears to be an additional risk factor for the development of atherosclerosis, including diseases in the coronary, cerebrovascular, and peripheral arteries (Willerson and Ridker, 2004; Prodanovich et al., manuscript submitted). This inflammatory process is characterized by the upregulation of the T helper 1–mediated cytokine cascade (including interferon (IFN)-γ, tumor necrosis factor-α, IL-1, and IL-6), which might ultimately trigger the acute coronary syndrome (Hansson, 2005).
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IL12 may play a critical role in chronic inflammatory processes, such those observed in psoriasis and those that trigger and propagate vascular disease, such as coronary artery disease (CAD). In this scenario, IL-12 plays a central role by driving immune responses toward T helper 1–type responses, including high IFN-γ and low IL-4 production. IFN-γ may be of special interest. Elevated plasma levels of IL-12 correlate with IFN-γ and IFN-γ-inducible chemokines, thus defining an IFN-γ axis that appears to be activated independently of IL-6 or C-reactive protein (Ranjbaran et al., 2007). While activation of the IFN-γ axis has not yet been associated with acute coronary syndromes, it did predict, on 1-year follow-up in patients with CAD, increased morbidity and mortality (Ranjbaran et al., 2007). On the basis of these results, the researchers concluded that circulating IL-12 may provide a mechanistic link between inflammation and T helper 1–type cytokine production in patients with CAD. While the cytokine milieu associated with psoriasis and CAD is probably complex, it appears that IL-12 may be pivotal in linking the chronic systemic inflammatory processes of psoriasis to the onset and propagation of vascular disease. Overall, these findings suggest that IL-12 and its inducible chemokines are involved in the psoriatic and coronary disease process and may lead to the onset and propagation of atherothrombosis. Recent data suggest that this immunologic link may help explain the epidemiologic findings associating these two diseases/processes. Patients who have psoriasis with genetic alterations in IL12 or 23 might be at even greater risk of CAD than other subsets of patients. 7. The results of this study suggest the potential for a number of further lines of clinical and bench research. For example, psoriasis may not be a single disease but rather a reaction pattern. Understanding the differing genetic bases in subpopulations of patients with psoriasis may help to predict the course of the disease. Therefore, understanding the genetic profile of patients with psoriasis and observing both their natural history and their responses to treatment are worthwhile. Future studies could further evaluate specific SNPs; for example, SNP knockout mice could be used to evaluate both the treatment and the severity of psoriasis. Unique models might enable further study of the relationship between psoriasis and other inflammatory diseases. Confirmatory and more in-depth genotyping could be performed to determine whether different types of psoriasis—or its severity—are linked to the SNPs confirmed in this study. REFERENCES Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L et al. (2007) Sequence variants in the genes for the interleukin-23 receptor (IL23R_) and its ligand (_IL12B) confer protection against psoriasis. Hum Genet 122:201–6 Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–90 Chang YT, Chou CT, Yu CW, Lin MW, Shiao YM, Chen CC et al. (2007) Cytokine gene polymorphisms in Chinese patients with psoriasis. Br J Dermatol 156:899–905 Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–3 Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S et al. (2001) Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357:1925–8 Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–95 Henselers T, Christophers E (1995). Disease concomitance in psoriasis. J Am Acad Dermatol 32:982–6 Hugot JP (2006) CARD15/NOD2 mutations in Crohn’s disease. Ann NY Acad Sci 1072:9–18 Krueger GG, Langley RG, Leonardi C et al. (2007) A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356:580–92 Lee FI, Bellary SV, Francis C (1990) Increased occurrence of psoriasis in patients with Crohn’s disease and their relatives [comments]. Am J Gastroenterol 85:962–3 Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch S et al. (2006) Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 78:827–51 Nair RP, Ruether A, Stuart PE, Jenisch S, Tejasvi T, Hiremagalore R et al. (2008) Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J Invest Dermatol 128:1653–61 Najarian DJ, Gottlieb AB (2003) Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol 48:805–21 Nickoloff BJ (2007) Cracking the cytokine code in psoriasis. Nat Med 13:242–4 Rahman P, Bartlett S, Siannis F, Pellett FJ, Farewell VT, Peddle L et al. (2003) CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet 73:677–81 Ranjbaran H, Sokol SI, Gallo A, Eid RE, Iakimov AO, D’Alessio A et al. (2007) An inflammatory pathway of IFN-gamma production in coronary atherosclerosis. J Immunol 178:592–604 Shastry BS (2007) SNPs in disease gene mapping, medicinal drug development and evolution. J Hum Genet 52:871–80
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Torti DC, Feldman SR (2007) Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 57:1059–68 Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H et al. (2002) Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30:161–6 Willerson JT, Ridker PM (2004) Inflammation as a cardiovascular risk factor. Circulation 109:II2–10 Wolf N, Quaranta M, Prescott NJ, Allen M, Smith R, Burden AD et al. (2008) Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease. J Med Genet 45:114–6 Yamada R (2008) Primer: SNP-associated studies and what they can teach us. Nat Clin Pract Rheumatol 4:210–7 1
Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
Updated 27 Jan 2009 14:40 UTC
© 2009 Nature Publishing Group
8/10/2009 1:42 PM
For the article: http://dx.doi.org/10.1038/sj.jid.5701255 For discussion and answers: http://network.nature.com/group/jidclub
Genetic Alterations in Psoriasis Deborah Zell1, Shasa Hu1 and Robert Kirsner1 Journal of Investigative Dermatology (2008), 128, 1614. doi:10.1038/jid.2008.160
The genetic basis of psoriasis has long been recognized, including the knowledge that family members of patients with psoriasis are at greater risk of developing the disease (Henselers and Christophers, 1995). Several lines of evidence suggest that genes regulating IL-12 and IL-23 may be important in its pathogenesis. Part of the rationale stems from observations indicating that patients with psoriasis and those with Crohn’s disease share common features: patients with Crohn’s disease are five times more likely than the general population to have psoriasis, and both diseases respond to anti–tumor necrosis factor-α therapy (Lee et al., 1990). A recent genomewide association scan identified a highly significant association between Crohn’s disease and a single-nucleotide polymorphism (SNP) in the coding region of the IL23R gene (Duerr et al., 2006), suggesting that this polymorphism might be present in patients with psoriasis. Additional studies from several diverse ethnic populations throughout the world have determined that psoriasis is associated with SNPs in IL-12 and IL-23 or their receptors (Capon et al., 2007; Cargill et al., 2007; Chang et al., 2007; Tsunemi et al., 2002). On the basis of the above information, Nair et al. (2008) studied four candidate SNPs in a large (more than 4,000 persons) cohort of white North American and German subjects with psoriasis and in controls. Two of the SNPs were the IL12B haplotype rs3212227 and rs6887695; the other two were IL23R haplotype rs7530511 and rs11209026. Nair et al. found that both IL12B markers had a highly significant association with psoriasis (odds ratio (OR) 1.62 and 1.49 for rs3212227 and rs6887695, respectively). The IL23R SNPs also demonstrated significant associations in the cases and controls (OR 1.22 and 1.40 for rs7530511 and rs11209026, respectively). These SNPs were not found to have interactions with a known genetic risk factor, HLA-Cw6. Through the following questions, we examine this paper in greater detail. For brief answers, please refer to http:// network.nature.com/group/jidclub. REFERENCES
Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L et al. (2007) Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet 122:201–6 Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–90 Chang YT, Chou CT, Yu CW, Lin MW, Shiao YM, Chen CC et al. (2007) Cytokine gene polymorphisms in Chinese patients with psoriasis. Br J Dermatol 156:899– 905 Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–3 Henselers T, Christophers E (1995). Disease concomitance in psoriasis. J Am Acad Dermatol 32:982–6 Lee FI, Bellary SV, Francis C (1990) Increased occurrence of psoriasis in patients with Crohn’s disease and their relatives [comments]. Am J Gastroenterol 85:962–3 Nair RP, Ruether A, Stuart PE, Jenisch S, Tejasvi T, Hiremagalore R et al. (2008) Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J Invest Dermatol 128: 1653–61 Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H et al. (2002) Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30:161–6
QUESTIONS 1. What is a single-nucleotide polymorphism (SNP)? 2. What data support an association between Crohn’s disease and psoriasis? 3. Why are IL12B and IL23R candidates for study? 4. How was the study performed? 5. What were the major findings of this study? 6. What may be the clinical implications of this study, and how may they change the way we think about the genetics of psoriasis? 7. What future studies might extend these findings? 1
Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
1614 Journal of Investigative Dermatology (2008), Volume 128
© 2008 The Society for Investigative Dermatology
July 2008 Journal Club Article: Genetic Alterations in Psoriasis from Jour...
1 of 4
http://network.nature.com/groups/jidclub/forum/topics/2057
Journal of Investigative Dermatology Journal Club
July 2008 Journal Club Article: Genetic Alterations in Psoriasis
Topic Article Polymorphisms of the IL12B and IL23R Genes Are Associated with Psoriasis Rajan P. Nair, Andreas Ruether, Philip E. Stuart, Stefan Jenisch, Trilokraj Tejasvi, Ravi Hiremagalore, Stefan Schreiber, Dieter Kabelitz, Henry W. Lim, John J. Voorhees, Enno Christophers, James T. Elder and Michael Weichenthal Journal of Investigative Dermatology (2008) 128, 1653-61; doi:10.1038/sj.jid.5701255 Genetic Alterations in Psoriasis Deborah Zell 1, Shasa Hu 1 and Robert Kirsner 1 Journal of Investigative Dermatology (2008), 128, 1614. doi:10.1038/jid.2008.160 The genetic basis of psoriasis has long been recognized, including the knowledge that family members of patients with psoriasis are at greater risk of developing the disease (Henselers and Christophers, 1995). Several lines of evidence suggest that genes regulating IL-12 and IL-23 may be important in its pathogenesis. Part of the rationale stems from observations indicating that patients with psoriasis and those with Crohn’s disease share common features: patients with Crohn’s disease are five times more likely than the general population to have psoriasis, and both diseases respond to anti–tumor necrosis factor-α therapy (Lee et al., 1990). A recent genome-wide association scan identified a highly significant association between Crohn’s disease and a single-nucleotide polymorphism (SNP) in the coding region of the IL23R gene (Duerr et al., 2006), suggesting that this polymorphism might be present in patients with psoriasis. Additional studies from several diverse ethnic populations throughout the world have determined that psoriasis is associated with SNPs in IL-12 and IL-23 or their receptors (Capon et al., 2007; Cargill et al., 2007; Chang et al., 2007; Tsunemi et al., 2002). On the basis of the above information, Nair et al. (2008) studied four candidate SNPs in a large (more than 4,000 persons) cohort of white North American and German subjects with psoriasis and in controls. Two of the SNPs were the IL12B haplotype rs3212227 and rs6887695; the other two were IL23R haplotype rs7530511 and rs11209026. Nair et al. found that both IL12B markers had a highly significant association with psoriasis (odds ratio (OR) 1.62 and 1.49 for rs3212227 and rs6887695, respectively). The IL23R SNPs also demonstrated significant associations in the cases and controls (OR 1.22 and 1.40 for rs7530511 and rs11209026, respectively). These SNPs were not found to have interactions with a known genetic risk factor, HLA-Cw6. Through the following questions, we examine this paper in greater detail. QUESTIONS 1. What is a single-nucleotide polymorphism (SNP)? 2. What data support an association between Crohn’s disease and psoriasis? 3. Why are IL12B and IL23R candidates for study? 4. How was the study performed? 5. What were the major findings of this study? 6. What may be the clinical implications of this study, and how may they change the way we think about the genetics of psoriasis? 7. What future studies might extend these findings? ANSWERS 1. A single-nucleotide polymorphism (SNP) occurs when one nucleotide in the genome sequence is substituted for another. SNPs occur relatively frequently and may occur anywhere in the gene sequence. A SNP within an individual’s genome leads to differences in the paired chromosomes in that individual. For a variation to be viewed as a SNP, by definition it must occur in more than 1% of a large population. SNPs are not homogeneous among populations, however, and a SNP allele common in one geographical or ethnic group may be much rarer in another (Yamada, 2008).
8/10/2009 1:42 PM
July 2008 Journal Club Article: Genetic Alterations in Psoriasis from Jour...
2 of 4
http://network.nature.com/groups/jidclub/forum/topics/2057
The mere presence of a SNP does not necessarily mean that a disease will result. For instance, a change in a single nucleotide may not result in a change in an amino acid. Owing to degeneracy of the genetic code, multiple-nucleotide triplets may code for the same amino acid, in which case the SNP is termed “synonymous,” or a silent mutation. Although a SNP may occur in a noncoding sequence, this does not imply that the variation will not result in disease, as SNPs in non-protein-coding regions may affect gene splicing, among other activities (Shastry, 2007). 2. Both psoriasis and Crohn’s disease are systemic inflammatory conditions. These diseases share a strong, albeit multifactorial, genetic basis, and both disorders respond well to tumor necrosis-α inhibitors (Najarian and Gottlieb, 2003). Patients with Crohn’s disease are five times more likely to have psoriasis than controls, suggesting a genetic link (Lee et al., 1990). The CARD15 gene has been convincingly associated with Crohn’s disease (Hampe et al., 2001; Hugot, 2006), and in one study it was associated with psoriatic arthritis (Rahman et al., 2003), supporting the notion of a shared genetic predisposition for the two diseases. In this and other studies, whole-genome association studies have identified two non–major histocompatibility complex disease genes (IL12B and IL23R), both of which also confer susceptibility to Crohn’s disease. In a recent case–control study of patients with Crohn’s disease and psoriasis, analysis of 1,256 patients and 2,938 unrelated controls revealed significant associations for loci mapping to chromosomes 1q24, 6p22, and 21q22 (Wolf et al., 2008). Interestingly, CDKAL1, a gene also associated with type 2 diabetes, was mapped to one purportedly involved SNP, rs6908425. These results support evidence for a pleiotropic role for multiple genes that contribute to the pathogenesis of both psoriasis and Crohn’s disease and—potentially—other immune-related diseases. 3. Recent studies have found an association between both IL12B and IL23R and psoriasis. Duerr et al. (2006) performed a genome-wide association scan that identified a highly significant association between a SNP in the IL23R gene (rs11209026) and Crohn’s disease. In addition, Cargill et al. (2007) performed a gene-centric genome-wide association scan in psoriasis, identifying a significant association with SNPs in the IL12B gene (which encodes for the p40-subunit common in both interleukin (IL)-12 and IL-23) and SNP rs1129026 in IL23. During the course of this study, two other discoveries confirmed associations with IL12B in psoriasis (Tsunemi et al., 2002) and IL12B and IL23R in psoriasis (Capon et al., 2007; Chang et al., 2007). 4. The authors performed a genetic epidemiology study. The application of high-quality genetic testing in association with classic epidemiologic methods provides a powerful tool for understanding population genetics. Using tissue from patients with psoriasis from centers in Ann Arbor, Michigan, and Kiel, Germany, or tissue provided by the National Psoriasis Foundation Tissue Bank, a case–control methodology was performed. The case–control sample included 360 cases and 1,097 controls from Kiel, as well as 1,450 cases and 1,425 controls from Ann Arbor. All cases had either plaque or guttate psoriasis, and both cases and controls were of European Caucasian ancestry. In a typical case–control study, risk factors for disease are analyzed to determine whether certain factors are more likely to be seen in cases than in controls. In this study, the risk factor for disease development was each individual’s “exposure” to a specific SNP. For each patient and control, DNA was prepared from peripheral blood mononuclear cells or Epstein–Barr virus–immortalized lymphoblastoid cell lines. SNPs were genotyped by single-base primer extension as implemented in the SnapShot assay protocol or by using the TaqMan allelic discrimination method (Nair et al., 2006). In addition to the four SNPs for the IL12B and IL23R genes, seven SNPs in exons 2 and 3 of the HLA-C gene were also typed, in order to provide unambiguous HLACw6 genotypes even in the absence of phasing (Nair et al., 2006). 5. This study confirmed the findings of other recently published work. In this study, highly significant associations between psoriasis and both IL12B and IL23R were found in a large Caucasian sample. Of the two, IL12B was found to be associated with a higher increased risk (25-fold) than IL23R (16-fold). Further, genetic epidemiology analysis was performed among members of affected families. In the familial analysis, the investigators found positive results for IL12B, but they were unable to confirm the case–control results for IL23R. This lends further support to the relative importance of IL12B. Since other genes have been associated with an increased risk of developing psoriasis, it was important to determine whether the findings were novel or due to interaction with other known genetic risk factors. Specifically, HLA-Cw6 is well known to be associated with psoriasis. However, in this study, no statistical evidence of interaction between IL12B and IL23R and HLA-Cw6 was demonstrated. This finding supports that IL12B and IL23R are associated with psoriasis and independent of HLA-Cw6. 6. In addition to providing a better understanding of the genetics of psoriasis, this paper may eventually prove to have several unexpected implications. Emerging data have implicated IL-12 and IL-23 in the pathogenesis of psoriatic lesions and the involvement of a unique T-cell subset, T-IL-17 (Nickoloff, 2007; Torti and Feldman 2007). This finding may have a genetic basis, and as a consequence may help to explain the epidemiologic association between psoriasis and vascular disease. This work may also explain recent therapeutic advances, particularly the initial success of an anti-IL-12/23 p40 monoclonal antibody therapy for psoriasis (Krueger et al., 2007). Similar to psoriasis, atherosclerosis may be a chronic inflammatory disease of the arterial wall. Disease may result as a consequence of the intricate interplay among several cellular and humoral immunologic factors (Willerson and Ridker, 2004). The presence of psoriasis—and systemic inflammation such as that seen in psoriasis—appears to be an additional risk factor for the development of atherosclerosis, including diseases in the coronary, cerebrovascular, and peripheral arteries (Willerson and Ridker, 2004; Prodanovich et al., manuscript submitted). This inflammatory process is characterized by the upregulation of the T helper 1–mediated cytokine cascade (including interferon (IFN)-γ, tumor necrosis factor-α, IL-1, and IL-6), which might ultimately trigger the acute coronary syndrome (Hansson, 2005).
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IL12 may play a critical role in chronic inflammatory processes, such those observed in psoriasis and those that trigger and propagate vascular disease, such as coronary artery disease (CAD). In this scenario, IL-12 plays a central role by driving immune responses toward T helper 1–type responses, including high IFN-γ and low IL-4 production. IFN-γ may be of special interest. Elevated plasma levels of IL-12 correlate with IFN-γ and IFN-γ-inducible chemokines, thus defining an IFN-γ axis that appears to be activated independently of IL-6 or C-reactive protein (Ranjbaran et al., 2007). While activation of the IFN-γ axis has not yet been associated with acute coronary syndromes, it did predict, on 1-year follow-up in patients with CAD, increased morbidity and mortality (Ranjbaran et al., 2007). On the basis of these results, the researchers concluded that circulating IL-12 may provide a mechanistic link between inflammation and T helper 1–type cytokine production in patients with CAD. While the cytokine milieu associated with psoriasis and CAD is probably complex, it appears that IL-12 may be pivotal in linking the chronic systemic inflammatory processes of psoriasis to the onset and propagation of vascular disease. Overall, these findings suggest that IL-12 and its inducible chemokines are involved in the psoriatic and coronary disease process and may lead to the onset and propagation of atherothrombosis. Recent data suggest that this immunologic link may help explain the epidemiologic findings associating these two diseases/processes. Patients who have psoriasis with genetic alterations in IL12 or 23 might be at even greater risk of CAD than other subsets of patients. 7. The results of this study suggest the potential for a number of further lines of clinical and bench research. For example, psoriasis may not be a single disease but rather a reaction pattern. Understanding the differing genetic bases in subpopulations of patients with psoriasis may help to predict the course of the disease. Therefore, understanding the genetic profile of patients with psoriasis and observing both their natural history and their responses to treatment are worthwhile. Future studies could further evaluate specific SNPs; for example, SNP knockout mice could be used to evaluate both the treatment and the severity of psoriasis. Unique models might enable further study of the relationship between psoriasis and other inflammatory diseases. Confirmatory and more in-depth genotyping could be performed to determine whether different types of psoriasis—or its severity—are linked to the SNPs confirmed in this study. REFERENCES Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L et al. (2007) Sequence variants in the genes for the interleukin-23 receptor (IL23R_) and its ligand (_IL12B) confer protection against psoriasis. Hum Genet 122:201–6 Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–90 Chang YT, Chou CT, Yu CW, Lin MW, Shiao YM, Chen CC et al. (2007) Cytokine gene polymorphisms in Chinese patients with psoriasis. Br J Dermatol 156:899–905 Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–3 Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S et al. (2001) Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357:1925–8 Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–95 Henselers T, Christophers E (1995). Disease concomitance in psoriasis. J Am Acad Dermatol 32:982–6 Hugot JP (2006) CARD15/NOD2 mutations in Crohn’s disease. Ann NY Acad Sci 1072:9–18 Krueger GG, Langley RG, Leonardi C et al. (2007) A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356:580–92 Lee FI, Bellary SV, Francis C (1990) Increased occurrence of psoriasis in patients with Crohn’s disease and their relatives [comments]. Am J Gastroenterol 85:962–3 Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch S et al. (2006) Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 78:827–51 Nair RP, Ruether A, Stuart PE, Jenisch S, Tejasvi T, Hiremagalore R et al. (2008) Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J Invest Dermatol 128:1653–61 Najarian DJ, Gottlieb AB (2003) Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol 48:805–21 Nickoloff BJ (2007) Cracking the cytokine code in psoriasis. Nat Med 13:242–4 Rahman P, Bartlett S, Siannis F, Pellett FJ, Farewell VT, Peddle L et al. (2003) CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet 73:677–81 Ranjbaran H, Sokol SI, Gallo A, Eid RE, Iakimov AO, D’Alessio A et al. (2007) An inflammatory pathway of IFN-gamma production in coronary atherosclerosis. J Immunol 178:592–604 Shastry BS (2007) SNPs in disease gene mapping, medicinal drug development and evolution. J Hum Genet 52:871–80
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Torti DC, Feldman SR (2007) Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 57:1059–68 Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H et al. (2002) Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30:161–6 Willerson JT, Ridker PM (2004) Inflammation as a cardiovascular risk factor. Circulation 109:II2–10 Wolf N, Quaranta M, Prescott NJ, Allen M, Smith R, Burden AD et al. (2008) Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease. J Med Genet 45:114–6 Yamada R (2008) Primer: SNP-associated studies and what they can teach us. Nat Clin Pract Rheumatol 4:210–7 1
Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
Updated 27 Jan 2009 14:40 UTC
© 2009 Nature Publishing Group
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