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Association between IL13 Polymorphisms and Psoriatic Arthritis Is Modified by Smoking

      Genetic and environmental factors influence the development of psoriasis (Ps) and psoriatic arthritis (PsA). Recently, we reported that three IL13 polymorphisms, rs1800925, rs20541, and rs848, on chromosome 5q31 conferred the risk for Ps. IL13 encodes IL-13, a Th2 cytokine, and rs1800925 and rs20541 confer risk of asthma. Further, smoking may increase the risk of developing Ps. We examined the association between IL13 polymorphisms, smoking, and PsA in two Ps sample sets genotyped for rs1800925, rs20541, and rs848. We found that the minor alleles (rs1800925*T, rs20541*A, and rs848*A) were significantly associated with protection from PsA versus controls, and that no association with Ps is seen when the PsA cases are excluded. This effect was strongest with rs1800925*T (odds ratio (OR) 0.40, Pallelic 0.000067). The prevalence of PsA in cases with the rs1800925*CT or TT genotype is about half that of those with the CC genotype (15.5 vs 32.1%, P=0.0002). However, smoking appears to abrogate this effect (CT/TT/non-smoker, prevalence of PsA 13%, OR 0.20, P=0.0001; CT/TT/smoker, prevalence 38%, OR 0.88, P=0.74, CC/non-smoker, prevalence 42% (reference), CC/smoker prevalence 47%, OR 1.21, P=0.47). This study suggests that IL13 polymorphisms associate most strongly with PsA and that smoking may modulate this effect.

      Abbreviations

      CI
      confidence interval
      COPD
      chronic obstructive pulmonary disease
      OR
      odds ratio
      Ps
      psoriasis
      PsA
      psoriatic arthritis

      Introduction

      Genetic and environmental factors are known to influence the development and phenotypic features of psoriasis (Ps) and psoriatic arthritis (PsA). Twin concordance studies and familial clustering of Ps are well known and support a strong genetic component (
      • Brandrup F.
      • Holm N.
      • Grunnet N.
      • Henningsen K.
      • Hansen H.E.
      Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution.
      ). HLA-Cw*0602, which lies in the PSORS1 risk locus on chromosome 6, is believed to confer the greatest risk of Ps of any locus (
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • Hiremagalore R.
      • Chia N.V.
      • Jenisch S.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ). However, this genetic risk factor is also strongly correlated with environmental factors that augment the Ps phenotype, including streptococcal pharyngitis, which is associated with guttate Ps in HLA-Cw0602-positive patients and Ps induced by trauma (Koebner phenomenon) (
      • Gudjonsson J.E.
      • Thorarinsson A.M.
      • Sigurgeirsson B.
      • Kristinsson K.G.
      • Valdimarsson H.
      Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study.
      ,
      • Gudjonsson J.E.
      • Karason A.
      • Runarsdottir E.H.
      • Antonsdottir A.A.
      • Hauksson V.B.
      • Jonsson H.H.
      • et al.
      Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients.
      ;
      • Holm S.J.
      • Sakuraba K.
      • Mallbris L.
      • Wolk K.
      • Stahle M.
      • Sanchez F.O.
      Distinct HLA-C/KIR genotype profile associates with guttate psoriasis.
      ). Recently, a case–control study in a Chinese population found a several fold increase in the risks of Ps in patients who smoke or have stressful life events and carry HLA-Cw6 (
      • Jin Y.
      • Yang S.
      • Zhang F.
      • Kong Y.
      • Xiao F.
      • Hou Y.
      • et al.
      Combined effects of HLA-Cw6 and cigarette smoking in psoriasis vulgaris: A hospital-based case-control study in China.
      ). Tobacco use and other environmental factors such as obesity have also been shown to be risk factors for the development of Ps (
      • Setty A.R.
      • Curhan G.
      • Choi H.K.
      Smoking and the risk of psoriasis in women: Nurses′ Health Study II.
      ).
      Psoriatic arthritis, which develops in 6–42% of patients with Ps (
      • Gelfand J.M.
      • Gladman D.D.
      • Mease P.J.
      • Smith N.
      • Margolis D.J.
      • Nijsten T.
      • et al.
      Epidemiology of psoriatic arthritis in the population of the United States.
      ), is also thought to have a strong and complex genetic basis. PsA has been associated with numerous HLA antigens, including HLA-Cw*0602 (
      • Gladman D.D.
      • Farewell V.T.
      HLA studies in psoriatic arthritis: current situation and future needs.
      ), HLA-B27, and others, as well as several outside of the major histocompatibility complex (reviewed by
      • Duffin K.C.
      • Chandran V.
      • Gladman D.D.
      • Krueger G.G.
      • Elder J.T.
      • Rahman P.
      Genetics of psoriasis and psoriatic arthritis: update and future direction.
      ). Similar to Ps, certain markers associate with PsA phenotype: patients who have HLA-Cw*0602 and HLA-DRB1*07 typically have a less severe course (
      • Ho P.Y.
      • Barton A.
      • Worthington J.
      • Thomson W.
      • Silman A.J.
      • Bruce I.N.
      HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriatic arthritis.
      ); patients with HLA-B27 tend to have spinal manifestations, whereas carriers of HLA-B38 and HLA-B39 tend to have more peripheral involvement (
      • Gladman D.D.
      • Farewell V.T.
      HLA studies in psoriatic arthritis: current situation and future needs.
      ). More recently, HLA-Cw*0602 has been shown to associate only with PsA in patients with younger age of onset of Ps (
      • Ho P.Y.
      • Barton A.
      • Worthington J.
      • Plant D.
      • Griffiths C.E.
      • Young H.S.
      • et al.
      Investigating the role of the HLA-Cw*06 and HLA-DRB1 genes in susceptibility to psoriatic arthritis: comparison with psoriasis and undifferentiated inflammatory arthritis.
      ). It has been speculated that trauma may increase the risk of developing PsA, perhaps the equivalent of the Koebner phenomenon in skin (
      • Ryan G.M.
      Psoriatic arthritis and Koebner phenomenon.
      ;
      • Pattison E.
      • Harrison B.J.
      • Griffiths C.E.
      • Silman A.J.
      • Bruce I.N.
      Environmental risk factors for the development of psoriatic arthritis: results from a case-control study.
      ). Although familial clustering has been observed in PsA (
      • Moll J.M.
      • Wright V.
      Familial occurrence of psoriatic arthritis.
      ), a recent study of twins in Denmark showed equivalent rates of monozygotic and dizygotic twin concordance, suggesting that environmental triggers may have a large role in the development of PsA (
      • Pedersen O.B.
      • Svendsen A.J.
      • Ejstrup L.
      • Skytthe A.
      • Junker P.
      On the heritability of psoriatic arthritis. Disease concordance among monozygotic and dizygotic twins.
      ). Little is known about gene–environment interaction in PsA.
      In the past 3 years, genome-wide case–control association studies have identified several new genetic polymorphisms that confer risk of Ps and PsA. Polymorphisms in IL12B, IL23R, and IL13 have been shown by our group and others to confer modest risk of Ps (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Smith R.L.
      • Warren R.B.
      • Eyre S.
      • Ho P.
      • Ke X.
      • Young H.S.
      • et al.
      Polymorphisms in the IL-12beta and IL-23R Genes Are Associated with Psoriasis of Early Onset in a UK Cohort.
      ;
      • Li Y.
      • Chang M.
      • Schrodi S.J.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Civello D.
      • et al.
      The 5q31 variants associated with psoriasis and Crohn′s disease are distinct.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ;
      • Chang M.
      • Li Y.
      • Yan C.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Garcia V.E.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ). Although it is now apparent that IL12B and IL23R genes encode cytokines and cytokine receptors that are important in the pathogenesis of Ps, the functional or causative roles for these polymorphisms are not known, and the role of IL13 in Ps is particularly unclear (
      • Duffin K.C.
      • Krueger G.G.
      Genetic Variations in Cytokines and Cytokine Receptors Associated with Psoriasis Found by Genome-Wide Association.
      ).
      IL13, located on chromosome 5q31, encodes the cytokine IL-13. Four polymorphisms in the IL13/IL4 region, including rs1800925, located 1kb 5′ of the IL13 coding region, rs20541 (a missense polymorphism in exon 4, Q144R), rs848 (in the 3′UTR), and rs11568506 (located in an intron of SLC22A4), have been shown to associate with Ps in a genome-wide study and follow-up fine-mapping study of our Utah sample set (
      • Li Y.
      • Chang M.
      • Schrodi S.J.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Civello D.
      • et al.
      The 5q31 variants associated with psoriasis and Crohn′s disease are distinct.
      ;
      • Chang M.
      • Li Y.
      • Yan C.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Garcia V.E.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ); association of rs20541 and rs848 with Ps was also seen in the Genetics Association Information Network genome-wide study of Ps (
      • Nair R.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kB pathways.
      ). IL-13, a Th2 cytokine, is not known to be expressed in psoriatic skin, but it has been found in the synovial fluid of patients with PsA (
      • Spadaro A.
      • Rinaldi T.
      • Riccieri V.
      • Valesini G.
      • Taccari E.
      Interleukin 13 in synovial fluid and serum of patients with psoriatic arthritis.
      ). IL-13 has an important role in Th2-mediated immune disorders such as asthma and chronic obstructive pulmonary disease (COPD), and IL13 polymorphisms rs1800925 and rs20541 are associated with the risk of asthma and COPD (
      • Heinzmann A.
      • Mao X.Q.
      • Akaiwa M.
      • Kreomer R.T.
      • Gao P.S.
      • Ohshima K.
      • et al.
      Genetic variants of IL-13 signalling and human asthma and atopy.
      ). There is also increasing evidence that there may be a gene–environment interaction between IL13 polymorphisms and tobacco that affects the clinical features of Th2 disorders. Homozygosity of the minor allele (T) of rs1800925 is associated with increased risk for smokers to develop diminished FEV1, FEV1/FVC ratio, and COPD when compared with smokers carrying the common C allele (
      • Sadeghnejad A.
      • Meyers D.A.
      • Bottai M.
      • Sterling D.A.
      • Bleecker E.R.
      • Ohar J.A.
      IL13 promoter polymorphism 1112C/T modulates the adverse effect of tobacco smoking on lung function.
      ). Children with the common haplotype of three IL13 polymorphisms, which include rs1800925 and rs20541, are more likely to develop asthma if exposed to smoking by their mothers in utero (
      • Sadeghnejad A.
      • Karmaus W.
      • Arshad S.H.
      • Kurukulaaratchy R.
      • Huebner M.
      • Ewart S.
      IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study.
      ).
      As smoking is considered a risk factor for the development of Ps, we hypothesized that there may be an association between the IL13 polymorphisms that confer risk of Ps, tobacco use, and phenotypic features of Ps. In addition, as data from our sample set have also shown that certain characteristics, such as age of onset of PsA, can be influenced by smoking history (
      • Rakkhit T.
      • Wong B.
      • Nelson T.S.
      • Hansen C.B.
      • Papenfuss J.S.
      • Panko J.
      • et al.
      Time to development of psoriatic arthritis decreases with smoking prior to psoriasis onset and increases with smoking after psoriasis onset.
      ), we specifically sought to examine the possible interaction between smoking and IL13 polymorphisms on the development of PsA.

      Results

      Demographics

      Of the 698 Utah cases that had been genotyped and were eligible for analysis, 181 had PsA, and 447 had cutaneous Ps only. Seventy cases were excluded on the grounds of having an equivocal arthritis diagnosis. Of the 447 cases with Ps only, 334 had Ps ≥10 years without PsA. Baseline characteristics of the 334 patients with Ps ≥10 years and the 181 PsA patients are shown in Table 1. There was a marginally significant trend for more females to have PsA, and for more males to have Ps only (P=0.048). The mean age of Ps onset in the Ps group was not statistically different from the PsA group (22.7±14.4 vs 25.9±14.3). The mean age of onset of the PsA was 37.5 years, and the mean duration of PsA was 13.1 years. The prevalence of smoking was 32.1% in the Ps only group, and 38.9% in the PsA group (P=0.12).
      Table 1Demographics of Utah cases with psoriasis ≥10years without PsA compared with cases with PsA
      Ps≥10years without PsA (n=334)PsA (n=181)P-value
      Male/female, N (%)179 (53.6%)/155 (46.4%)80 (44.4%)/100(55.6%)0.048
      Mean age of onset of Ps (years)22.7±14.425.9±14.3NS
      Mean age of onset of PsA (years)NA37.5±14.4NA
      Mean duration of PsA (years)NA13.1±12.4NA
      Prevalence of smoking32.1%38.9%0.12
      NA, not applicable; Ps, psoriasis; PsA, psoriatic arthritis.

      The minor allele of rs1800925 associates with protection from PsA

      Recently, we have shown association of Ps with four polymorphisms in the IL13/IL4 region: rs1800925 (located in the 5′ promoter region), rs20541 (located within exon 4 of IL13), rs848 (located in the 3′UTR), and rs11568506 (located in an intron of SLC22A4) (
      • Li Y.
      • Chang M.
      • Schrodi S.J.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Civello D.
      • et al.
      The 5q31 variants associated with psoriasis and Crohn′s disease are distinct.
      ;
      • Chang M.
      • Li Y.
      • Yan C.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Garcia V.E.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ). Although many other single-nucleotide polymorphisms (SNPs) in the region associate with Ps, analysis taking into account linkage disequilibrium showed that rs1800925 and rs11568506 independently confer risk, and rs11568506 is only marginally significant. Therefore, we sought to determine whether a correlation existed between the polymorphisms that conferred the most risk (rs1800925) and clinical features of Ps. We found that PsA was less frequent in cases with the rs1800925*CT or TT genotype compared with the CC genotype (15.5 vs 32.1%, P=0.0002, odds ratios (OR)=0.38) (Table 2). Other phenotypic features, including gender, age of onset of Ps, and mean age of onset of PsA, were not statistically different.
      Table 2Clinical features of psoriasis cases with genotype rs1800925 CC versus CT/TT
      rs1800925CC (n=337)CT/TT (123)P-value
      Male/female (%)49/5152/480.56
      Mean age of onset of Ps28.5±16.329.2±18.10.71
      PsA108 (32.1%)19 (15.5%)0.0002
      Mean age onset of PsA38.6±14.635.0±13.90.32
      Smokers128 (38.1%)48 (39.0%)0.86
      Ps, psoriasis; PsA, psoriatic arthritis.
      This finding prompted us to further analyze the relationship between PsA and the IL13 polymorphisms. The cases were divided into three groups: PsA, cutaneous Ps only (“Ps”), and cutaneous Ps for ≥10 years without PsA; allele and genotype frequencies for rs1800925, rs20541, and rs848 were compared for each group with the non-psoriatic controls (Table 3). This analysis revealed that the minor allele of all three SNPs was significantly associated with protection from PsA, which was most pronounced for rs1800925 (OR 0.40, 95% confidence interval (CI) 0.25–0.65, Pallelic=0.000067, Pgenotypic=0.00014). Interestingly, the allele frequencies in the Ps only group and Ps ≥10 years group are identical to that of controls. To confirm this, we performed the same analysis in the GCI sample set provided by Celera Corporation (Alameda, CA) in which the necessary phenotypic data (number of years with Ps and diagnosis of PsA) were available (Table 3). This analysis also showed that the rs1800925*T was protective in the PsA group of the GCI sample set (OR 0.53, 95% CI 0.33–0.83, Pallelic=0.0025, Pgenotypic=0.008).
      Table 3Association of IL13 polymorphisms rs1800925, rs20541, and rs848 with PsA and psoriasis without PsA compared with controls in the Utah sample set
      MarkerStatusGenotypeOR (95% CI)
      All statistics compare sample set to control.
      PAllelic
      Allelic P-values were performed using Fisher's exact test.
      PGenotypic
      Genotypic P-values were performed using William's corrected log-likelihood ratio tests. P-values are two-tailed, except for the GCI sample, for which P-values are one-tailed as the hypothesis for this analysis was defined by the direction of the allelic effect in the Utah samples.
      rs1800295CCCTTT
      UPI samplePsA (127)108 (0.85)17 (0.13)2 (0.02)0.40 (0.25, 0.65)0.0000670.00014
      Ps (283)
      Ps sample set includes the “Ps≥10years” sample set.
      193 (0.68)82 (0.29)8 (0.03)1.07 (0.81,1.41)0.680.88
      Ps≥10years (208)141 (0.67)61 (0.29)6 (0.03)0.95 (0.70, 1.29)0.760.94
      Control (456)303 (0.66)139 (0.30)14 (0.03)
      Rs1800295CCCTTT
      GCI samplePsA (98)76 (0.78)21 (0.21)1 (0.01)0.53 (0.33, 0.83)0.00250.008
      Ps (396)
      Ps sample set includes the “Ps≥10years” sample set.
      259 (0.65)129 (0.33)8 (0.02)0.89 (0.70, 1.12)0.830.92
      Ps≥10years (143)94 (0.66)46 (0.32)3 (0.02)0.88 (0.63, 1.23)0.250.23
      Control (495)316 (0.64)158 (0.32)21 (0.04)
      Rs20541GGGAAA
      UPI samplePsA (181)135 (0.75)42 (0.23)4 (0.02)0.66 (0.47, 0.92)0.0150.051
      Ps (447)
      Ps sample set includes the “Ps≥10years” sample set.
      294 (0.66)142 (0.32)11 (0.02)1.09 (0.86, 1.38)0.510.28
      Ps≥10years (334)220 (0.66)105 (0.31)9 (0.03)0.92 (0.72, 1.19)0.560.46
      Control (458)298 (0.65)140 (0.31)20 (0.04)
      Rs848CCCAAA
      UPI samplePsA (178)132 (0.74)42 (0.24)4 (0.02)0.65 (0.47, 0.92)0.0150.047
      Ps (437)
      Ps sample set includes the “Ps≥10years” sample set.
      285 (0.65)141 (0.32)11 (0.03)1.09 (0.86, 1.38)0.510.40
      Ps≥10years (329)216 (0.66)104 (0.32)9 (0.03)0.91 (0.71, 1.18)0.520.56
      Control (458)294 (0.64)145 (0.32)19 (0.04)
      CI, confidence interval; GCI, Genomics Collaborative Division of SeraCare Life Sciences; OR, odds ratio; Ps, psoriasis; PsA, psoriatic arthritis; UPI, Utah Psoriasis Initiative.
      1 All statistics compare sample set to control.
      2 Allelic P-values were performed using Fisher's exact test.
      3 Genotypic P-values were performed using William's corrected log-likelihood ratio tests. P-values are two-tailed, except for the GCI sample, for which P-values are one-tailed as the hypothesis for this analysis was defined by the direction of the allelic effect in the Utah samples.
      4 Ps sample set includes the “Ps≥10years” sample set.

      Effect of smoking and rs1800925 alleles on risk of PsA

      As noted in previous studies, smoking appears to alter the risk and severity of COPD depending on which alleles of IL13 are present. We hypothesized that smoking could modulate the protection from PsA in patients carrying rs1800925*T. For this analysis, the prevalence of PsA was determined in four groups: non-smokers with genotype CT or TT, smokers with CT or TT, non-smokers with CC, and smokers with CC (Table 4). The prevalence of PsA in non-smokers with CT or TT was 13%, compared with 38% in smokers with CT or TT. In contrast, the prevalence of PsA in non-smokers with the CC genotype was 42%, and it was 47% in smokers with CC. We conclude that smoking appears to abrogate the protective effect of rs1800925*T, such that the prevalence of PsA among patients who smoke with the rs1800925*T is comparable with the prevalence of PsA in non-smoking patients with the common risk allele (CT/TT/non-smoker, prevalence of PsA 13%, OR 0.20, P=0.0001; CT/TT/smoker, prevalence 38%, OR 0.88, P=0.74, CC/non-smoker, prevalence 42% (reference), CC/smoker prevalence 47%, OR 1.21, P=0.47).
      Table 4Prevalence of PsA in smokers and nonsmokers with CC versus CT/TT genotypes
      rs1800925SmokingPsAOR (95% CI)P-value
      Standard one-way analysis of variance was performed for comparisons among the groups defined by smoking status and genotype.
      CT/TT-7/55 (13%)0.20 (0.08–0.48)0.0001
      CT/TT+12/31 (38%)0.88 (0.39–1.93)0.74
      CC-67/160 (42%)ReferenceReference
      CC+41/88 (47%)1.21 (072–2.05)0.47
      CI, confidence interval; OR, odds ratio; Ps, psoriasis; PsA, psoriatic arthritis.
      1 Standard one-way analysis of variance was performed for comparisons among the groups defined by smoking status and genotype.

      Effect of smoking on onset of PsA

      Previously, we reported that smoking appeared to prolong the time to development of PsA in the Utah sample set (
      • Rakkhit T.
      • Wong B.
      • Nelson T.S.
      • Hansen C.B.
      • Papenfuss J.S.
      • Panko J.
      • et al.
      Time to development of psoriatic arthritis decreases with smoking prior to psoriasis onset and increases with smoking after psoriasis onset.
      ). To determine whether smoking and rs1800925 influence the time to development of PsA, we performed an interaction analysis using one-way analysis of variance (Table 5). Time from the development of Ps to PsA was determined in smokers and non-smokers with or without rs1800925*T. The analysis showed that smoking was associated with delayed onset of PsA: non-smokers with genotype CT or TT developed PsA 8.83±12.43 years after the onset of Ps, compared with 17.57±14.49 years for smokers; similarly, non-smokers with genotype CC developed PsA 12.43 years ±11.28 after the onset of Ps, compared with 16.37±13.10 years in smokers (P=0.013). Interaction of smoking and rs1800925 for delaying onset of PsA, however, did not reach statistical significance (P=0.08).
      Table 5Mean time to development of PsA in smokers and non-smokers with rs1800925 CC versus CT/TT genotypes
      Rs1800925Smoking
      The interaction of genotype and smoking on mean number of years from Ps onset to PsA onset was performed using one-way analysis of variance. Smoking was associated with the delayed onset of PsA (P=0.013). The interaction of smoking and the rs1800925 polymorphism had borderline significance (P=0.08).
      Mean no. of years from Ps onset to PsA onset
      The interaction of genotype and smoking on mean number of years from Ps onset to PsA onset was performed using one-way analysis of variance. Smoking was associated with the delayed onset of PsA (P=0.013). The interaction of smoking and the rs1800925 polymorphism had borderline significance (P=0.08).
      CT/TT-8.83±12.43
      CT/TT+17.57±14.49
      CC-12.43±11.28
      CC+16.37±13.10
      Ps, psoriasis; PsA, psoriatic arthritis.
      1 The interaction of genotype and smoking on mean number of years from Ps onset to PsA onset was performed using one-way analysis of variance. Smoking was associated with the delayed onset of PsA (P=0.013). The interaction of smoking and the rs1800925 polymorphism had borderline significance (P=0.08).

      Discussion

      These results show that the minor alleles of three IL13 polymorphisms, rs1800925*T, rs20541*A, and rs848*A, associate with protection from PsA in patients with Ps. Previously, our group has reported association of Ps from four polymorphisms within the IL13/IL4 region: rs1800925*T, rs20541*A, rs848*A, and the SLC22A4 intronic SNP rs11568506. We initially reported that the risk haplotype (CCG) of rs1800925, rs20541, and rs848 conferred risk with a combined OR of 1.27 (Pcombined=1.88 × 10−4) (
      • Chang M.
      • Li Y.
      • Yan C.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Garcia V.E.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ). The follow-up study (
      • Li Y.
      • Chang M.
      • Schrodi S.J.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Civello D.
      • et al.
      The 5q31 variants associated with psoriasis and Crohn′s disease are distinct.
      ) examined 106 polymorphisms in the IL13/IL4 region and concluded that rs1800925 could account for observed significant association of all but one other SNP, rs11568506 in SLC22A4, which alone conferred only modest risk. However, these studies only compared cases with Ps with non-psoriatic controls. Our data suggest that the association of the IL13 SNPs with Ps appears to be driven by the association with PsA. This conclusion is based on data that show that the allele frequencies in the groups where PsA cases were removed are nearly identical to that of controls.
      Two other large-scale genome-wide studies of Ps, which included PsA sample sets in the analysis, have recently been published. The Genetics Association Information Network study, a genome-wide association of 1409 cases and 1436 controls that included the Utah sample set from this study, also reported the association of rs20541 with Ps. The replication phase of this study supported the association of rs20541 with Ps and PsA, but a comparison of allele frequencies for rs20541 between PsA cases and cutaneous Ps only was not significant (P=0.11) (
      • Nair R.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kB pathways.
      ). It is noted that this study did not include rs1800925, which is in moderate linkage disequilibrium with rs20541 (r2=0.24). The genome-wide study reported by
      • Liu Y.
      • Helms C.
      • Liao W.
      • Zaba L.C.
      • Duan S.
      • Gardner J.
      • et al.
      A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.
      , which used a relatively small discovery set of 223 cases, including 91 PsA patients, also did not find association of Ps or PsA with SNPs in the 5q31 region. Certainly, the size of the study populations, differences in genetic architecture across populations, different environmental influences, and the modest contribution of the IL13 polymorphisms may have contributed to the lack of power to find association of IL13 SNPs with PsA in these studies. Further replication of our association of PsA with rs1800925 is needed to confirm this finding.
      The biological role of IL13 polymorphisms and IL-13 in the development of Ps or PsA remains unclear. No identified functional role exists for rs1800925, which lies near the 5′ end of IL13. This SNP, along with rs11568506, marks a risk haplotype, and it is possible that an unidentified or untested variant along this haplotype may be the true risk variant. However, IL13 remains an interesting inflammatory disease candidate, given the role that IL-13 has in the Th2-mediated allergic inflammatory response seen in asthma, allergy, helminthic responses, and atopic dermatitis (
      • Lee J.S.
      • Rosengart M.R.
      • Kondragunta V.
      • Zhang Y.
      • McMurray J.
      • Branch R.A.
      • et al.
      Inverse association of plasma IL-13 and inflammatory chemokines with lung function impairment in stable COPD: a cross-sectional cohort study.
      ). IL-13 has not been detected in psoriatic skin, but increased synovial IL-13 levels have been reported in patients with PsA and rheumatoid arthritis (
      • Spadaro A.
      • Rinaldi T.
      • Riccieri V.
      • Valesini G.
      • Taccari E.
      Interleukin 13 in synovial fluid and serum of patients with psoriatic arthritis.
      ). Several in vivo and animal studies have suggested that IL-13 has protective effects related to inflammatory arthropathy, including the following: (1) inhibition of tumor necrosis factor-α activation of osteoclasts, (2) inhibition of cartilage destruction by downregulating activity of matrix metalloproteinases and blocking apoptosis of chondrocytes, (3) inhibition of angiogenesis thereby preventing overgrowth of tortuous blood vessels within the synovium and (4) inhibition of the production of inflammatory cytokines by monocytes obtained from peripheral blood (
      • Woods J.M.
      • Amin M.A.
      • Katschke Jr., K.J.
      • Volin M.V.
      • Ruth J.H.
      • Connors M.A.
      • et al.
      Interleukin-13 gene therapy reduces inflammation, vascularization, and bony destruction in rat adjuvant-induced arthritis.
      ;
      • Palmqvist P.
      • Lundberg P.
      • Persson E.
      • Johansson A.
      • Lundgren I.
      • Lie A.
      • et al.
      Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway.
      ;
      • Haas C.S.
      • Amin M.A.
      • Ruth J.H.
      • Allen B.L.
      • Ahmed S.
      • Pakozdi A.
      • et al.
      In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis.
      ). Although these findings do not clarify the role of elevated levels of IL-13 in PsA, it is possible that IL-13 in the synovium counteracts the Th1-mediated inflammatory milieu in PsA.
      There is also increasing evidence that a correlation exists between IL13 genotype, IL-13 expression, and smoking in a variety of disease states. Our study is the first to suggest that protection from PsA conferred by rs1800925*T could be negated by a current or past smoking history. This protective effect of the minor alleles of IL13 polymorphisms, which included rs1800925, has also been shown in children who were exposed to tobacco smoke in utero; children carrying the minor alleles have less severe wheezing than those who carried the common haplotype. However, in smokers who develop COPD, it appears that it is the common allele rather than the minor allele that protects from more severe airflow obstruction.
      The results of this study also show that smoking is associated with delaying the onset of PsA in patients with Ps. This finding has interesting parallels to inflammatory bowel disease, which similar to Ps is influenced by smoking and common genetic variants. In Crohn's disease, tobacco use is associated with later onset of disease and a more severe course; in contrast, in ulcerative colitis, smoking is associated with a less severe clinical course and decreased need for corticosteroids and colectomy (
      • Calkins B.M.
      A meta-analysis of the role of smoking in inflammatory bowel disease.
      ;
      • Mokbel M.
      • Carbonnel F.
      • Beaugerie L.
      • Gendre J.P.
      • Cosnes J.
      Effect of smoking on the long-term course of ulcerative colitis.
      ;
      • Mahid S.S.
      • Minor K.S.
      • Soto R.E.
      • Hornung C.A.
      • Galandiuk S.
      Smoking and inflammatory bowel disease: a meta-analysis.
      ,
      • Mahid S.S.
      • Minor K.S.
      • Stevens P.L.
      • Galandiuk S.
      The role of smoking in Crohn′s disease as defined by clinical variables.
      ). Crohn's disease is also associated with polymorphisms in the IL13/IL4 region (though distinct from the Ps risk polymorphisms) (
      • Wellcome Trust Case Control Consortium
      Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
      ;
      • Li Y.
      • Chang M.
      • Schrodi S.J.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Civello D.
      • et al.
      The 5q31 variants associated with psoriasis and Crohn′s disease are distinct.
      ) and the same polymorphism in IL23R that associates with Ps (
      • Duerr R.H.
      • Taylor K.D.
      • Brant S.R.
      • Rioux J.D.
      • Silverberg M.S.
      • Daly M.J.
      • et al.
      A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ). It is clear that further studies are needed to determine the relationship between susceptibility genes such as IL13 and smoking in immune-mediated disorders and overlapping genetic and environmental triggers such as Ps and inflammatory bowel disease.
      Previous studies have examined the effect of smoking on the development of inflammatory joint disease. Meta-analysis of epidemiologic studies has suggested that smoking may increase the risk for development of rheumatoid factor positive rheumatoid arthritis (
      • Sugiyama D.
      • Kunihiro N.
      • Kenichiro T.
      • Goh T.
      • Takashi N.
      • Akio M.
      • et al.
      Impact of smoking as a risk factor for developing rheumatoid arthritis: A meta-analysis of observational studies.
      ). The effect of smoking on the development of rheumatoid factor positive rheumatoid arthritis is influenced by gender, having a more profound effect in males than females. In addition,
      • Padyukov L.
      • Silva C.
      • Stolt P.
      • Alfredsson L.
      • Klaresko L.
      A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis.
      showed a gene–environment interaction for rheumatoid factor positive rheumatoid arthritis. In this study, the risk gene, a shared HLA-DRB1 epitope, conferred even greater risk in current smokers compared with non-smokers (relative risk=2.8 (95% CI 1.6–4.8) for non-smokers versus relative risk=15.7 (95% CI 7.2–34.2) for current smokers).
      There are several limitations to our study that must be considered when interpreting the results. First, the diagnosis of PsA in all participants was self-reported as having been diagnosed by a rheumatologist. We did not have a rheumatologist independently confirm the diagnosis; however, all patients were seen by dermatologists trained in assessing PsA, and equivocal cases were excluded from the study. In addition, no data were collected on disease severity, joints affected, or subclassification of PsA. Our “Ps only” subsets may also have included patients who have undiagnosed PsA or will go on to develop it. We chose to limit this possibility by creating a set of psoriasis cases who have had Ps for at least 10 years without PsA, as it is reported that most patients who will develop PsA do so within the first 10 years (
      • Gladman D.D.
      • Antoni C.
      • Mease P.
      • Clegg D.O.
      • Nash P.
      Psoriatic arthritis: epidemiology, clinical features, course, and outcome.
      ). The diagnosis, or lack of diagnosis of PsA, could also have been confounded by treatment history, which we did not take into account. Systemic therapies such as methotrexate or biological agents could have masked clinical signs or symptoms of PsA, thus decreasing the likelihood of detecting PsA, or even reducing the likelihood of developing PsA despite a genetic or environmental predisposition. Yet another limitation of the study was that smoking history was not quantified in a detailed manner, which prevented our ability to identify a dose-dependent relationship of smoking to PsA. Evaluation of additional sample sets in an attempt to replicate these results is imperative for strong conclusions to be drawn. Prospectively enrolled databases of patients with psoriatic disease with detailed clinical information, including rheumatologic examination and detailed smoking history, are needed to confirm these data.
      In summary, our data suggest that polymorphisms in the IL13/IL4 region, a previously identified autoimmune susceptibility locus, may associate with PsA more than Ps with cutaneous manifestations alone, and this susceptibility may be influenced by smoking history. This study supports the hypothesis that genes and environment may interact to influence the development of PsA. Further studies are needed to confirm our findings and to elucidate the biological pathways influenced by IL13 and tobacco use.

      Materials and Methods

      Utah participants

      Detailed demographic and clinical data as well as genotype data were obtained from participants with Ps enrolled in the Utah Ps Initiative. This study was approved by the University of Utah Institutional Review Board and conducted according to the Declaration of Helsinki principles. All participants provided written informed consent and had been recruited from dermatology clinics affiliated with the University of Utah. Enrollment included completion of a questionnaire, detailed physical examination, an interview by a trained research physician, and collection of a peripheral blood sample for DNA extraction.
      All eligible participants from the Utah Psoriasis Initiative were examined and confirmed to have Ps. Patients were considered to have PsA if the patient reported that a rheumatologist had diagnosed PsA. Equivocal cases of PsA were excluded from the analysis. Smoking history was obtained by patient self-report on the intake questionnaires. Patients were considered smokers if they answered “yes” to the question,“ have you ever smoked cigarettes on a routine basis?”
      The replication study population was collected by the Genomics Collaborative Division of SeraCare Life Sciences (GCI) as described elsewhere (
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ). The patients in this study set had dermatologist-confirmed Ps. Presence of PsA, age of onset of Ps, and age of onset of PsA had also been dermatologist-reported.
      For the association analysis, the Ps sample sets were divided into three groups: cases with Ps and PsA (“PsA”), cases with Ps without PsA regardless of duration of Ps (“Ps”), and cases with Ps for ≥10 years without PsA (“Ps≥10years”). The 10-year cutoff was arbitrarily chosen to create a set of patients who were less likely to develop PsA, given that most patients develop PsA within the first 10 years of developing Ps (
      • Gladman D.D.
      • Antoni C.
      • Mease P.
      • Clegg D.O.
      • Nash P.
      Psoriatic arthritis: epidemiology, clinical features, course, and outcome.
      ).

      Genotyping

      All genotyping was performed at Celera Corporation. Genotyping methodology and the association of Ps with the three IL13 polymorphisms, rs1800925 (5′ promoter), rs20541 (exon 4), and rs848 (3′UTR) in the 467 Utah patients and 460 controls and GCI replication sample set (495 cases, 495 controls) are described in our previous publications (
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Chang M.
      • Li Y.
      • Yan C.
      • Callis-Duffin K.P.
      • Matsunami N.
      • Garcia V.E.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ). An additional 233 patients from the Utah Psoriasis Initiative were also genotyped for rs20541and rs848 as part of the replication effort of the Genetics Association Information Network genome-wide association study of Ps (
      • Nair R.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kB pathways.
      ).

      Statistical analysis

      Allelic OR and 95% CI were calculated by comparison of the total number of each allele found among cases and controls. P-value testing for differences in allele frequencies and genotype frequencies were calculated using Fisher's exact test (for allelic P-values) and William's corrected log-likelihood ratio test. T-tests were used to compare the means of quantitative variables between cases and controls and standard one-way analysis of variance was performed for comparisons among multiple groups defined by smoking status and genotype. One-way analysis of variance was used to determine the effect of the interaction of smoking and genotype on the delay of onset of PsA. All significance tests were two-sided, with the exception of the association analysis in the replication group, which was one-sided as the hypothesis for this analysis was defined by the direction of the allelic effect in the Utah samples. Statistical analyses were performed using STATA 9.0 (Stata Corp., College Station, TX).

      Conflict of Interest

      Steven J. Schrodi is employed by and owns stock in Celera Corporation, Alameda, CA.

      ACKNOWLEDGMENTS

      We would like to thank Christopher Hansen, Jason Papenfuss, Jackie Panko, Matthew Hoffman, and Tyler Nelson for their work in enrolling the patients into the Utah Psoriasis Initiative. We would also like to thank Celera Corporation, the National Institutes of Health, and the Genetic Association Information Network for their ongoing support of this work.

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