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Association of TNF -238 and -308 Promoter Polymorphisms with Psoriasis Vulgaris and Psoriatic Arthritis but not with Pustulosis Palmoplantaris

2005; Elsevier BV; Volume: 124; Issue: 1 Linguagem: Inglês

10.1111/j.0022-202x.2004.23556.x

1523-1747

Rotraut Mößner, Külli Kingo, André Kleensang, Ullrich Krüger, Inke R. König, Helgi Silm, Götz Westphal, Kristian Reich,

Dermatology and Skin Diseases

confidence interval odds ratio adjusted p value nominal p value psoriasis area and severity index pustulosis palmoplantaris psoriatic arthritis psoriasis vulgaris tumor necrosis factor To the Editor: Overexpression of tumor necrosis factor (TNF)-α is a central element in the pathogenesis of psoriasis vulgaris (PV) and psoriatic arthritis (PsA); however, the underlying mechanisms are poorly understood. Several recent studies with German patients found an association between the rare *A allele of the G→A single nucleotide polymorphism at position -238 of the TNFA promoter and psoriasis, particularly in patients with early disease onset (Arias et al., 1997Arias A.I. Giles B. Eiermann T.H. Sterry W. Pandey J.P. Tumor necrosis factor-alpha gene polymorphism in psoriasis.Exp Clin Immunogenet. 1997; 14: 118-122PubMed Google Scholar; Hohler et al., 1997Hohler T. Kruger A. Schneider P.M. et al.A TNF-alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis.J Invest Dermatol. 1997; 109: 562-565https://doi.org/10.1111/1523-1747.ep12337469Crossref PubMed Scopus (175) Google Scholar; Reich et al., 1999Reich K. Westphal G. Schulz T. et al.Combined analysis of polymorphisms of the tumor necrosis factor-alpha and interleukin-10 promoter regions and polymorphic xenobiotic metabolizing enzymes in psoriasis.J Invest Dermatol. 1999; 113: 214-220https://doi.org/10.1046/j.1523-1747.1999.00654.xCrossref PubMed Scopus (77) Google Scholar; Hohler et al., 2002Hohler T. Grossmann S. Stradmann-Bellinghausen B. et al.Differential association of polymorphisms in the TNFalpha region with psoriatic arthritis but not psoriasis.Ann Rheum Dis. 2002; 61: 213-218https://doi.org/10.1136/ard.61.3.213Crossref PubMed Scopus (52) Google Scholar; Reich et al., 2002Reich K. Mössner R. König I.R. Westphal G. Ziegler A. Neumann C. Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset.J Invest Dermatol. 2002; 118: 155-163https://doi.org/10.1046/j.0022-202x.2001.01642.xCrossref PubMed Scopus (100) Google Scholar). There is also evidence that carriage of the rare *A allele of another G→A single nucleotide polymorphism at position -308 of the promoter is decreased in patients with PsA (Hohler et al., 2002Hohler T. Grossmann S. Stradmann-Bellinghausen B. et al.Differential association of polymorphisms in the TNFalpha region with psoriatic arthritis but not psoriasis.Ann Rheum Dis. 2002; 61: 213-218https://doi.org/10.1136/ard.61.3.213Crossref PubMed Scopus (52) Google Scholar), although within this disease subgroup it may be increased in patients with a more progressive course of joint involvement (Balding et al., 2003Balding J. Kane D. Livingstone W. Mynett-Johnson L. Bresnihan B. Smith O. FitzGerald O. Cytokine gene polymorphisms: Association with psoriatic arthritis susceptibility and severity.Arthritis Rheum. 2003; 48: 1408-1413Crossref PubMed Scopus (116) Google Scholar). In light of the possible influence of TNFA promoter polymorphisms on cytokine production (Hajeer and Hutchinson, 2001Hajeer A.H. Hutchinson I.V. Influence of TNFalpha gene polymorphisms on TNFalpha production and disaease.Hum Immunol. 2001; 62: 1191-1199https://doi.org/10.1016/S0198-8859(01)00322-6Crossref PubMed Scopus (290) Google Scholar), the increased formation of TNF-α in psoriasis could at least partially be genetically determined. In this study, TNFA -238 and -308 genotypes were analyzed in 239 unrelated patients with PV, 43 patients with pustulosis palmoplantaris (PPP) without concomitant PV, and 135 control subjects according to published methods (Reich et al., 2002Reich K. Mössner R. König I.R. Westphal G. Ziegler A. Neumann C. Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset.J Invest Dermatol. 2002; 118: 155-163https://doi.org/10.1046/j.0022-202x.2001.01642.xCrossref PubMed Scopus (100) Google Scholar). All participants were Caucasians and were enrolled at the Department of Dermatology, University of Tartu, Estonia. Patients with PV were considered to have early-onset disease if skin symptoms occurred before 40 y of age, and late-onset disease if age at onset was ≥40 y (Henseler and Christophers, 1985Henseler T. Christophers E. Psoriasis of early and late onset: Characterization of two types of psoriasis vulgaris.J Am Acad Dermatol. 1985; 13: 450-456Abstract Full Text PDF PubMed Scopus (734) Google Scholar). Disease severity was assessed at study entry by determination of the psoriasis area and severity index (PASI) (Fredriksson and Pettersson, 1978Fredriksson T. Pettersson U. Severe psoriasis—oral therapy with a new retinoid.Dermatologica. 1978; 157: 238-244Crossref PubMed Scopus (2127) Google Scholar). PV patients were classified to have concomitant PsA (n=59) if this diagnosis had been established by an experienced rheumatologist. Clinical deformities of the hands and/or feet consistent with PsA were seen in 23 of these patients, and nine patients had erosions of the hands and/or feet by radiographic assessment. Control subjects were recruited from among medical students, health care personnel, and patients presenting at the dermatological outpatient clinic with mild expression of either facial teleangiectasis or skin tags. The study was approved by the Ethics Review Committee on Human Research of the University of Tartu, and was conducted according to the Declaration of Helsinki protocols. Informed consent was obtained from all participants. To evaluate deviation from the Hardy–Weinberg equilibrium, observed and expected genotype frequencies were compared by a Monte-Carlo goodness-of-fit test in PV and PPP patients and in controls. Odds ratios (OR) and exact 95% confidence intervals (CI) were calculated to compare genotype frequencies. Carriage rates of variant allele were investigated using the exact test by Fisher. To correct for multiple testing, a hierarchical test strategy was adhered to as described (Reich et al., 2002Reich K. Mössner R. König I.R. Westphal G. Ziegler A. Neumann C. Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset.J Invest Dermatol. 2002; 118: 155-163https://doi.org/10.1046/j.0022-202x.2001.01642.xCrossref PubMed Scopus (100) Google Scholar), and the respective nominal p values (pnom) were adjusted according to Bonferroni–Holm (padj). Absolute and relative TNFA genotype frequencies are shown in Table I. The genotypes were in Hardy–Weinberg equilibrium with the exception of the TNFA -238 locus in the PPP subgroup (p=0.0118). TNFA genotype frequencies in the control group were similar to those observed in other large European studies (Hohler et al., 1997Hohler T. Kruger A. Schneider P.M. et al.A TNF-alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis.J Invest Dermatol. 1997; 109: 562-565https://doi.org/10.1111/1523-1747.ep12337469Crossref PubMed Scopus (175) Google Scholar; Reich et al., 2002Reich K. Mössner R. König I.R. Westphal G. Ziegler A. Neumann C. Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset.J Invest Dermatol. 2002; 118: 155-163https://doi.org/10.1046/j.0022-202x.2001.01642.xCrossref PubMed Scopus (100) Google Scholar).Table IFrequencies of TNFA -238 and TNFA -308 genotypes in the investigated groupsPsoriasis vulgarisPPPControls(n=239)(n=43)(n=135)Genotypen (%)n (%)n (%)TNFA -238G/G182 (76.3)42 (97.7)123 (91.1)G/A55 (23.0)aOdds ratio=3.21, 95% confidence interval=1.60–6.84, nominal p-value=0.0003, adjusted p-value=0.0012; TNF -238*G/A and *A/A psoriasis vulgaris vs control.012 (8.9)A/A2 (0.8)1 (2.3)0TNFA -308G/G197 (82.4)32 (74.4)95 (70.4)G/A41 (17.2)bOdds ratio=0.51, 95% confidence interval=0.30–0.86, nominal p-value=0.0090, adjusted p-value=0.0360; TNF -308*G/A and *A/A psoriasis vulgaris vs control.11 (25.6)39 (28.9)A/A1 (0.4)01 (0.7)PPP, palmoplantar pustulosis.a Odds ratio=3.21, 95% confidence interval=1.60–6.84, nominal p-value=0.0003, adjusted p-value=0.0012; TNF -238*G/A and *A/A psoriasis vulgaris vs control.b Odds ratio=0.51, 95% confidence interval=0.30–0.86, nominal p-value=0.0090, adjusted p-value=0.0360; TNF -308*G/A and *A/A psoriasis vulgaris vs control. Open table in a new tab PPP, palmoplantar pustulosis. Carriage of TNFA -238*A was significantly more common among patients with PV than among control subjects (23.8%vs 8.9%; OR 3.21 [1.60–6.84], padj=0.0012), whereas carriage of TNFA -308*A was decreased (17.6%vs 29.6% in controls, OR 0.51 [0.30–0.86], padj=0.0360). The latter finding was independent of TNFA -238 as the difference between patients and controls remained similar after exclusion of -238*A positive individuals from the analysis (20.3%vs 30.9% in controls). Pathogenetic similarities between PV and PPP have recently been shown to include the prominent role of TNF-α (Kitamura et al., 1999Kitamura T. Tamada Y. Kato M. Yokochi T. Ikeya T. Soluble E-selectin as a marker of disease activity in pustulosis palmaris et plantaris.Acta Derm Venereol. 1999; 79: 462-464https://doi.org/10.1080/000155599750009924Crossref PubMed Scopus (11) Google Scholar). But, in contrast to the findings in PV patients, carriage rates of TNF -238*A and TNF -308*A in patients with PPP were similar to those in the control group (Table I). In accordance with previous findings, the association between TNFA -238*A and PV appeared to be more pronounced in patients with a positive family history (30.3%vs 8.9% in controls; OR 4.46 [2.05–10.14], padj=0.0036) than in those with sporadic disease (19.3%vs controls; OR 2.45 [1.13–5.56], pnom=0.0155, padj=0.1860). Unlike in earlier studies (Reich et al., 2002Reich K. Mössner R. König I.R. Westphal G. Ziegler A. Neumann C. Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset.J Invest Dermatol. 2002; 118: 155-163https://doi.org/10.1046/j.0022-202x.2001.01642.xCrossref PubMed Scopus (100) Google Scholar), however, TNFA -238*A was likewise increased in patients with early (<40 y) and late disease onset (≥40 y), and in male and female patients. The decrease of TNFA -308*A was seen in patients with early and late disease onset, and seemed to be independent of gender and family history. Due to the smaller number of individuals in the subgroup analysis, not all associations remained significant after correction for multiple testing. As there is recent evidence that cytokine gene polymorphisms may influence disease severity in PV and PsA (Balding et al., 2003Balding J. Kane D. Livingstone W. Mynett-Johnson L. Bresnihan B. Smith O. FitzGerald O. Cytokine gene polymorphisms: Association with psoriatic arthritis susceptibility and severity.Arthritis Rheum. 2003; 48: 1408-1413Crossref PubMed Scopus (116) Google Scholar; Kingo et al., 2003Kingo K. Koks S. Silm H. Vasar E. IL-10 promoter polymorphisms influence disease severity and course in psoriasis.Genes Immun. 2003; 4: 455-457https://doi.org/10.1038/sj.gene.6364004Crossref PubMed Scopus (42) Google Scholar), TNFA genotype frequencies were also analyzed separately in patient subgroups with mild (PASI<12; n=87) and moderate-to-severe disease (PASI≥12; n=152). Genotype frequencies of the TNFA -238 polymorphism were not significantly different in these groups. But, there was a trend toward a decreased carriage of TNFA -308*A in patients with more severe disease. In patients with mild disease, the carriage rate of the *A allele was 21.8%, and was not significantly different compared with control individuals (29.6%; OR=0.66 [0.33–1.29], pnom=0.2165), but it was 15.1% in patients with a PASI≥12 (OR=0.42 [0.23–0.78], pnom=0.0041, padj=0.1640 vs controls). Increased carriage of TNFA -238*A in PV patients compared with controls was more pronounced among patients without arthritis (25.6%vs 8.9% in controls; OR 3.52 [1.73–7.62], padj<0.0001) than among patients with arthritis (18.6%vs 8.9%; OR 2.35 [0.87–6.24], padj=0.4376), while the finding of a decreased carriage of TNFA -308*A was more pronounced among patients with arthritis (13.6%vs 29.6%; OR 0.37 [0.14–0.89], pnom=0.0187, padj=0.5236) than among patients without joint involvement (18.9%vs 29.6%; OR 0.55 [0.32–0.97], pnom=0.0316, padj=0.7584). Within the subgroup of patients with arthritis, however, TNFA -308*A appeared to be increased in individuals with more severe joint disease, i.e., patients with deformities of the hands and/or feet or radiologically confirmed erosions (Figure 1). In conclusion, we confirm and extend previous observations on the role of TNFA promoter polymorphisms in psoriasis and postulate that (i) carriage of TNFA -238*A is associated with PV in Caucasian populations, whereas carriage of TNFA -308*A may have a protective effect and is associated with less severe skin disease, that (ii) PPP, at least the PPP variant without concomitant PV, is genetically different from PV, and that (iii) although carriage of TNFA -308*A is decreased in PsA compared with controls, within patients with arthritis, it may be a marker of more severe joint involvement. With therapies that antagonize TNF-α becoming a more widely used strategy to treat psoriatic skin and joint symptoms, it will be interesting to see whether the presence of TNFA promoter polymorphisms influences the response to treatment. Our study supports the concept of a differential role of TNFA polymorphisms in PV and PsA and encourages future investigations in the field. We thank Melanie Walter, Pia Ballhausen, Sulev Kõks, and Ruth Pooga for excellent technical assistance.