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Polymorphisms in the IL-12β and IL-23R Genes Are Associated with Psoriasis of Early Onset in a UK Cohort

2007; Elsevier BV; Volume: 128; Issue: 5 Linguagem: Inglês

10.1038/sj.jid.5701140

1523-1747

Rhodri L. Smith, Richard B. Warren, Stephen Eyre, Pauline Ho, Xiayi Ke, Helen Young, C.E.M. Griffiths, Jane Worthington,

Asthma and respiratory diseases

genome-wide association study IL-23-receptor single nucleotide polymorphism. A recent genome-wide association study (GWAS) conducted 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: 273-290Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar reported an association between psoriasis and the IL-12β and IL-23R genes. Their study focused on the analysis of gene-centric single nucleotide polymorphisms (SNPs) identifying four non-HLA SNPs associated with psoriasis in a North American population. Our study confirms these findings in a single-point association study genotyping these four SNPs (two in the IL-12β gene and two in the IL-23R gene) in 597 UK psoriasis patients with onset of disease at ≤40 years of age (type I psoriasis; 53.6% male; 46.4% female; mean age of onset 19.8 years; 58.8% patients HLA-Cw6-positive). Recruitment of type I psoriasis patients for the case cohort was coordinated through the Dermatology Centre, Hope Hospital, The University of Manchester, Manchester, UK. All patients gave written informed consent and the study was approved by the Salford and Trafford Local Research Ethics Committee and conducted according to the Declaration of Helsinki Principles. Control data were available from the Wellcome Trust Case Control Consortium (rs6887695, rs11209026, and rs7530511) and 1958 British Birth Cohort study (rs3212227) (Power and Elliott, 2006Power C. Elliott J. Cohort profile: 1958 British birth cohort (National Child Development Study).Int J Epidemiol. 2006; 35: 34-41Crossref PubMed Scopus (704) Google Scholar). The SNP rs3212227, located in the IL-12β gene, which encodes the IL-12β-p40 subunit of the IL-12 and IL-23, was previously associated with the disease in a study of 143 Japanese psoriasis patients and 100 unaffected controls (P=0.035) (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) and also a recent independent GWAS of UK psoriasis patients (P=0.036) (Capon et al., 2007Capon F. Di M.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). Our findings replicate the associations found in the US (P=7.85 × 10−10; 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: 273-290Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar), Japanese, and UK cohorts with association to the same allele (P=0.003; Table 1) where risk was conferred by carriage of two copies of the major allele (genotype AA) with an odds ratio of 1.38 (95% CI 1.14–1.68; P=0.0004).Table 1Genotype frequencies in type I psoriasis patients and controlsSNPGenotypePatients n (%)Controls n (%)MAFMAF (Cargill et al.)HWE in controls1HWE: Hardy–Weinberg equilibrium statistics calculated in STATA 8.2 by comparing genotype frequencies expected under HWE against the observed genotype frequencies.P-valueTrend testrs3212227AA417 (71.77)3,032 (64.77)AC149 (25.65)1,478 (31.57)0.1940.2090.6080.0030.047CC15 (2.58)171 (3.65)rs6887695GG309 (52.46)1,343 (45.93)GC246 (41.77)1,303 (44.56)0.3180.3190.1470.0010.001CC34 (5.77)278 (9.51)rs11209026GG551 (92.61)2,569 (88.25)GA44 (7.39)342 (11.75)0.0600.0600.0010.0010.002AA0 (0)0 (0)rs7530511CC471 (86.11)1,118 (75.75)CT64 (11.70)333 (22.56)0.1300.1460.972<0.0010.476TT12 (2.19)25 (1.69)MAF, minor allele frequencies; SNP, single nucleotide polymorphism.1 HWE: Hardy–Weinberg equilibrium statistics calculated in STATA 8.2 by comparing genotype frequencies expected under HWE against the observed genotype frequencies. Open table in a new tab MAF, minor allele frequencies; SNP, single nucleotide polymorphism. The GWAS found association to a second SNP rs6887695 in IL-12β (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: 273-290Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar) and reported a haplotypic association. We also detected association to rs6887695, confirming this single-point genotypic association (P=0.001; Table 1) on the basis of a dominant model of inheritance for the major allele (genotype GG) with an odds ratio of 1.72 (95% CI 1.18–2.56; P=0.0016); however, we reported low linkage disequilibrium correlation with r2=0.21 (calculated using the genetic analysis software HelixTree; Golden Helix Inc., Bozeman, Montana) between these SNPs in the patient cohort and thus did not conduct any haplotype analysis. 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: 273-290Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar also investigated the IL-23 cytokine-related proteins (as IL-23R shares the IL-12β-p40 protein subunit) and identified two further SNPs in the IL-23 receptor gene (IL-23R) associated with psoriasis. SNP rs7530511 was detected in the single-point marker analysis of the GWAS with a P-value of 0.006, whereas SNP rs11209026 showed significant association to the disease in combination with this marker in an estimated haplotype analysis (P=3.3 × 10−6) (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: 273-290Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar), a finding replicated in the GWAS of UK psoriasis patients (P=0.00014) (Capon et al., 2007Capon F. Di M.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). Our study also confirms genotypic association to these markers with P<0.001 and P=0.001 for rs11209026 and rs7530511 SNPs, respectively (Table 1), with a dominant model of inheritance for the major allele in rs11209026 (genotype GG) with odds ratio of 1.67 (95% CI 1.20–2.37; P=0.0008) and risk conferred by carriage of two copies of the major allele in rs7530511 (genotype CC) with odds ratio of 1.98 (95% CI 1.51–2.63; P<0.0001). However, again we do not report any haplotype analysis for these markers, as we found no evidence of linkage disequilibrium correlation between rs11209026 and rs7530511 in the patient cohort (r2<0.01, again calculated using the HelixTree software). Interestingly, this gene had previously shown significant association to inflammatory bowel 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 (2446) Google Scholar), a condition showing comorbidity with psoriasis (prevalence of psoriasis 9.6% in inflammatory bowel disease patients compared to 2.2% of controls; 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). In summary, we have confirmed the associations to SNPs in both IL-12β and IL-23R detected in the GWAS of 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: 273-290Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar. Reassuringly, the minor allele frequencies for these SNPs are very similar in the controls of all three studies with the associations detected assigned to the same allele of the markers (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; Capon et al., 2007Capon F. Di M.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: 273-290Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar). Therefore, we conclude that IL-12β and IL-23R are key non-HLA genes in psoriasis and that further investigation and functional studies are required to determine how the variant forms of these genes influence the pathogenesis of the disease. It is interesting to note evidence that both IL-12β and IL-23R appear to play key roles in psoriasis. This evidence includes the observations that IL-23 induces epidermal hyperproliferation via tumor necrosis factor-α and IL-20 (Chan et al., 2006Chan J.R. Blumenschein W. Murphy E. Diveu C. Wiekowski M. Abbondanzo S. et al.IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.J Exp Med. 2006; 203: 2577-2587Crossref PubMed Scopus (553) Google Scholar), and suppressing the effects of IL-12/IL-23 with a monoclonal antibody to the shared p40 subunit is effective treatment for severe psoriasis (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). Investigations to elucidate the precise mechanisms by which these variants influence the psoriatic process may lead to further developments of novel therapeutics targeting this key pathway. C.E.M. Griffiths is a paid consultant to Centocor, Schering-Plough, UCB Pharma, Wyeth, and Merck-Serono. This project was supported by an unrestricted Stiefel PhD studentship, awarded to RhLLS (Stiefel Laboratories, Maidenhead, UK). Richard B. Warren is in receipt of a Clinical Research Training Fellowship from the Medical Research Council, UK (Grant fellowship – G0500449). We also acknowledge use of specimens from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02.