Light for Hope Foundation ®

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 et al., 1982).HLA-Cw*0602, which lies in thePSORS1risk locus on chromosome 6, is believed to confer the greatest risk of Ps of any locus (Nair et al., 2006). 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 inHLA-Cw0602-positive patients and Ps induced by trauma (Koebner phenomenon) (Gudjonsson et al., 2003,2006;Holm et al., 2005). 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 carryHLA-Cw6(Jin et al., 2008). Tobacco use and other environmental factors such as obesity have also been shown to be risk factors for the development of Ps (Setty et al., 2007).

Psoriatic arthritis, which develops in 6–42%of patients with Ps (Gelfand et al., 2005), is also thought to have a strong and complex genetic basis. PsA has been associated with numerous HLA antigens, includingHLA-Cw*0602(Gladman and Farewell, 2003),HLA-B27, and others, as well as several outside of the major histocompatibility complex (reviewed byDuffin et al., 2008). Similar to Ps, certain markers associate with PsA phenotype: patients who haveHLA-Cw*0602andHLA-DRB1*07typically have a less severe course (Ho et al., 2007); patients withHLA-B27tend to have spinal manifestations, whereas carriers ofHLA-B38andHLA-B39tend to have more peripheral involvement (Gladman and Farewell, 2003). More recently,HLA-Cw*0602has been shown to associate only with PsA in patients with younger age of onset of Ps (Ho, 2008). It has been speculated that trauma may increase the risk of developing PsA, perhaps the equivalent of the Koebner phenomenon in skin (Ryan, 1991;Pattison et al., 2008). Although familial clustering has been observed in PsA (Moll and Wright, 1973), 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 et al., 2008). 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 inIL12B, IL23R, andIL13have been shown by our group and others to confer modest risk of Ps (Capon et al., 2007;Cargill et al., 2007;Smith et al., 2007;Li et al., 2008;Nair et al., 2008;Chang et al., 2008). Although it is now apparent thatIL12BandIL23Rgenes 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 ofIL13in Ps is particularly unclear (Duffin and Krueger, 2008).

IL13, located on chromosome 5q31, encodes the cytokine IL-13. Four polymorphisms in theIL13/IL4region, including rs1800925, located 1kb 5′ of theIL13coding region, rs20541 (a missense polymorphism in exon 4, Q144R), rs848 (in the 3′UTR), and rs11568506 (located in an intron ofSLC22A4), have been shown to associate with Ps in a genome-wide study and follow-up fine-mapping study of our Utah sample set (Li et al., 2008;Chang et al., 2008); association of rs20541 and rs848 with Ps was also seen in the Genetics Association Information Network genome-wide study of Ps (Nair et al., 2009). 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 et al., 2002). IL-13 has an important role in Th2-mediated immune disorders such as asthma and chronic obstructive pulmonary disease (COPD), andIL13polymorphisms rs1800925 and rs20541 are associated with the risk of asthma and COPD (Heinzmann et al., 2000). There is also increasing evidence that there may be a gene–environment interaction betweenIL13polymorphisms 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 et al., 2007). Children with the common haplotype of threeIL13polymorphisms, which include rs1800925 and rs20541, are more likely to develop asthma if exposed to smoking by their mothersin utero(Sadeghnejad et al., 2008).

As smoking is considered a risk factor for the development of Ps, we hypothesized that there may be an association between theIL13polymorphisms 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 et al., 2007), we specifically sought to examine the possible interaction between smoking andIL13polymorphisms 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 Ps10 years without PsA. Baseline characteristics of the 334 patients with Ps10 years and the 181 PsA patients are shown inTable 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±14.4vs25.9±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 1 - Demographics of Utah cases with psoriasis 10 years without PsA compared with cases with PsA.

The minor allele of rs1800925 associates with protection from PsA

Recently, we have shown association of Ps with four polymorphisms in theIL13/IL4region: rs1800925 (located in the 5′ promoter region), rs20541 (located within exon 4 ofIL13), rs848 (located in the 3′UTR), and rs11568506 (located in an intron ofSLC22A4) (Li et al., 2008;Chang et al., 2008). 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 (15.5vs32.1%,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 2 - Clinical features of psoriasis cases with genotype rs1800925 CCversus CT/TT.

This finding prompted us to further analyze the relationship between PsA and theIL13polymorphisms. The cases were divided into three groups: PsA, cutaneous Ps only (“Ps”), and cutaneous Ps for10 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,P_allelic=0.000067,P_genotypic=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,P_allelic=0.0025,P_genotypic=0.008).

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 ofIL13are 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 4 - Prevalence of PsA in smokers and nonsmokers with CC versus CT/TT genotypes.

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 et al., 2007). 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 5 - Mean time to development of PsA in smokers and non-smokers with rs1800925 CC versus CT/TT genotypes.

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 threeIL13polymorphisms, 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 theIL13/IL4region: rs1800925^*T, rs20541^*A, rs848^*A, and theSLC22A4intronic SNP rs11568506. We initially reported that the risk haplotype (CCG) of rs1800925, rs20541, and rs848 conferred risk with a combined OR of 1.27 (P_combined=1.88 × 10⁻⁴) (Chang et al., 2008). The follow-up study (Li et al., 2008) examined 106 polymorphisms in theIL13/IL4region and concluded that rs1800925 could account for observed significant association of all but one other SNP, rs11568506 inSLC22A4, 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 theIL13SNPs 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 et al., 2009). 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 byLiu et al. (2008), 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 theIL13polymorphisms may have contributed to the lack of power to find association ofIL13SNPs with PsA in these studies. Further replication of our association of PsA with rs1800925 is needed to confirm this finding.

The biological role ofIL13polymorphisms 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 ofIL13. 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,IL13remains 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 et al., 2007). 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 et al., 2002). Severalin vivoand animal studies have suggested that IL-13 has protective effects related to inflammatory arthropathy, including the following: (1) inhibition of tumor necrosis factor-αactivation 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 et al., 2002;Palmqvist et al., 2006;Haas et al., 2007). 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 betweenIL13genotype, 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 ofIL13polymorphisms, which included rs1800925, has also been shown in children who were exposed to tobacco smokein 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, 1989;Mokbel et al., 1998;Mahid et al., 2006,2007). Crohn's disease is also associated with polymorphisms in theIL13/IL4region (though distinct from the Ps risk polymorphisms) (Wellcome Trust Case Control Consortium, 2007;Li et al., 2008) and the same polymorphism inIL23Rthat associates with Ps (Duerr et al., 2006;Cargill et al., 2007). It is clear that further studies are needed to determine the relationship between susceptibility genes such asIL13and 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 et al., 2009). 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 et al. (2004)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-smokersversusrelative 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 et al., 2005). 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 theIL13/IL4region, 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 byIL13and 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 et al., 2007). 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 (“Ps10years”). 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 et al., 2005).

Genotyping

All genotyping was performed at Celera Corporation. Genotyping methodology and the association of Ps with the threeIL13polymorphisms, 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 et al., 2007;Chang et al., 2008). 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 et al., 2009).

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 allelicP-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.

References

1. Brandrup F, Holm N, Grunnet N, Henningsen K, Hansen HE (1982) Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution.Acta Derm Venereol62:229–236 | PubMed | ISI | ChemPort |
2. Calkins BM (1989) A meta-analysis of the role of smoking in inflammatory bowel disease.Dig Dis Sci34:1841–1854 | Article | PubMed | ISI | ChemPort |
3. Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber Let al. (2007) Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.Hum Genet122:201–206 | Article | PubMed | ChemPort |
4. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KPet al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.Am J Hum Genet80:273–390 | Article | PubMed | ISI | ChemPort |
5. Chang M, Li Y, Yan C, Callis-Duffin KP, Matsunami N, Garcia VEet al. (2008) Variants in the 5q31 cytokine gene cluster are associated with psoriasis.Genes Immun9:176–181 | Article | PubMed | ChemPort |
6. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJet al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.Science314:1461–1463 | Article | PubMed | ISI | ChemPort |
7. Duffin KC, Chandran V, Gladman DD, Krueger GG, Elder JT, Rahman P (2008) Genetics of psoriasis and psoriatic arthritis: update and future direction.J Rheumatol35:1449–1453 | PubMed | ChemPort |
8. Duffin KC, Krueger GG (2008) Genetic Variations in Cytokines and Cytokine Receptors Associated with Psoriasis Found by Genome-Wide Association.J Invest Dermatol129:827–833 | Article | PubMed | ChemPort |
9. Gelfand JM, Gladman DD, Mease PJ, Smith N, Margolis DJ, Nijsten Tet al. (2005) Epidemiology of psoriatic arthritis in the population of the United States.J Am Acad Dermatol53:573 | Article | PubMed
10. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome.Ann Rheum Dis64(Suppl 2):ii14–ii17 | Article | PubMed
11. Gladman DD, Farewell VT (2003) HLA studies in psoriatic arthritis: current situation and future needs.J Rheumatol30:4–6 | PubMed |
12. Gudjonsson JE, Karason A, Runarsdottir EH, Antonsdottir AA, Hauksson VB, Jonsson HHet al. (2006) Distinct clinical differences between HLA-Cw^*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients.J Invest Dermatol126:740–745 | Article | PubMed | ChemPort |
13. Gudjonsson JE, Thorarinsson AM, Sigurgeirsson B, Kristinsson KG, Valdimarsson H (2003) Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study.Br J Dermatol149:530–534 | Article | PubMed | ISI | ChemPort |
14. Haas CS, Amin MA, Ruth JH, Allen BL, Ahmed S, Pakozdi Aet al. (2007)In vivoinhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis.Arthritis Rheum56:2535–2548 | Article | PubMed | ChemPort |
15. Heinzmann A, Mao XQ, Akaiwa M, Kreomer RT, Gao PS, Ohshima Ket al. (2000) Genetic variants of IL-13 signalling and human asthma and atopy.Hum Mol Genet9:549–559 | Article | PubMed | ISI | ChemPort |
16. Ho PY, Barton A, Worthington J, Thomson W, Silman AJ, Bruce IN (2007) HLA-Cw6 and HLA-DRB1^*07 together are associated with less severe joint disease in psoriatic arthritis.Ann Rheum Dis66:807–811 | Article | PubMed | ChemPort |
17. Ho PY, Barton A, Worthington J, Plant D, Griffiths CE, Young HSet al. (2008) Investigating the role of the HLA-Cw^*06 and HLA-DRB1 genes in susceptibility to psoriatic arthritis: comparison with psoriasis and undifferentiated inflammatory arthritis.Ann Rheum Dis67:677–682 | Article | PubMed | ChemPort |
18. Holm SJ, Sakuraba K, Mallbris L, Wolk K, Stahle M, Sanchez FO (2005) Distinct HLA-C/KIR genotype profile associates with guttate psoriasis.J Invest Dermatol125:721–730 | Article | PubMed | ChemPort |
19. Jin Y, Yang S, Zhang F, Kong Y, Xiao F, Hou Yet al. (2008) Combined effects of HLA-Cw6 and cigarette smoking in psoriasis vulgaris: A hospital-based case-control study in China.J Eur Acad Dermatol Venereol23:132–137 | Article | PubMed
20. Lee JS, Rosengart MR, Kondragunta V, Zhang Y, McMurray J, Branch RAet al. (2007) Inverse association of plasma IL-13 and inflammatory chemokines with lung function impairment in stable COPD: a cross-sectional cohort study.Respir Res8:64 | Article | PubMed | ChemPort |
21. Li Y, Chang M, Schrodi SJ, Callis-Duffin KP, Matsunami N, Civello Det al. (2008) The 5q31 variants associated with psoriasis and Crohn's disease are distinct.Hum Mol Genet17:2978–2985 | Article | PubMed | ChemPort |
22. Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner Jet al. (2008) A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.PLoS Genet4:1–14 | Article | ChemPort |
23. Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S (2006) Smoking and inflammatory bowel disease: a meta-analysis.Mayo Clin Proc81:1462–1471 | Article | PubMed
24. Mahid SS, Minor KS, Stevens PL, Galandiuk S (2007) The role of smoking in Crohn's disease as defined by clinical variables.Dig Dis Sci52:2897–2903 | Article | PubMed
25. Mokbel M, Carbonnel F, Beaugerie L, Gendre JP, Cosnes J (1998) Effect of smoking on the long-term course of ulcerative colitis.Gastroenterol Clin Biol22:858–862 | PubMed | ChemPort |
26. Moll JM, Wright V (1973) Familial occurrence of psoriatic arthritis.Ann Rheum Dis32:181–201 | Article | PubMed | ISI | ChemPort |
27. Nair R, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar Det al. (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kB pathways.Nat Genet41:199–204 | Article | PubMed | ChemPort |
28. Nair RP, Ruether A, Stuart PE, Jenisch S, Tejasvi T, Hiremagalore Ret al. (2008) Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.J Invest Dermatol128:1653–1661 | Article | PubMed | ChemPort |
29. Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch Set al. (2006) Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.Am J Hum Genet78:827–851 | Article | PubMed | ISI | ChemPort |
30. Padyukov L, Silva C, Stolt P, Alfredsson L, Klaresko L. (2004) A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis.Arthritis Rheum50:3085–3092 | Article | PubMed | ISI | ChemPort |
31. Palmqvist P, Lundberg P, Persson E, Johansson A, Lundgren I, Lie Aet al. (2006) 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.J Biol Chem281:2414–2429 | Article | PubMed | ChemPort |
32. Pattison E, Harrison BJ, Griffiths CE, Silman AJ, Bruce IN (2008) Environmental risk factors for the development of psoriatic arthritis: results from a case-control study.Ann Rheum Dis67:672–676 | Article | PubMed | ChemPort |
33. Pedersen OB, Svendsen AJ, Ejstrup L, Skytthe A, Junker P (2008) On the heritability of psoriatic arthritis. Disease concordance among monozygotic and dizygotic twins.Ann Rheum Dis67:1417–1421 | Article | PubMed | ChemPort |
34. Rakkhit T, Wong B, Nelson TS, Hansen CB, Papenfuss JS, Panko Jet al. (2007) Time to development of psoriatic arthritis decreases with smoking prior to psoriasis onset and increases with smoking after psoriasis onset.J Invest Derm127(Suppl 1): S52(abstract)
35. Ryan GM (1991) Psoriatic arthritis and Koebner phenomenon.J Hand Surg (Am)16:180–181 | PubMed | ChemPort |
36. Sadeghnejad A, Karmaus W, Arshad SH, Kurukulaaratchy R, Huebner M, Ewart S (2008) IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study.Respir Res9:2 | Article | PubMed | ChemPort |
37. Sadeghnejad A, Meyers DA, Bottai M, Sterling DA, Bleecker ER, Ohar JA (2007) IL13 promoter polymorphism 1112C/T modulates the adverse effect of tobacco smoking on lung function.Am J Respir Crit Care Med176:748–752 | Article | PubMed | ChemPort |
38. Setty AR, Curhan G, Choi HK (2007) Smoking and the risk of psoriasis in women: Nurses' Health Study II.Am J Med120:953–959 | Article | PubMed
39. Smith RL, Warren RB, Eyre S, Ho P, Ke X, Young HSet al. (2007) Polymorphisms in the IL-12beta and IL-23R Genes Are Associated with Psoriasis of Early Onset in a UK Cohort.J Invest Dermatol128:1325–1327 | Article | PubMed | ChemPort |
40. Spadaro A, Rinaldi T, Riccieri V, Valesini G, Taccari E (2002) Interleukin 13 in synovial fluid and serum of patients with psoriatic arthritis.Ann Rheum Dis61:174–176 | Article | PubMed | ChemPort |
41. Sugiyama D, Kunihiro N, Kenichiro T, Goh T, Takashi N, Akio Met al. (2009) Impact of smoking as a risk factor for developing rheumatoid arthritis: A meta-analysis of observational studies.Ann Rheum Dis; 1–17, advance online publication, 28 Jan 2009 (DOI: 10.1136/ard.2008.096487) | Article
42. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature447:661–678 | Article | PubMed | ISI | ChemPort |
43. Woods JM, Amin MA, Katschke KJ Jr, Volin MV, Ruth JH, Connors MAet al. (2002) Interleukin-13 gene therapy reduces inflammation, vascularization, and bony destruction in rat adjuvant-induced arthritis.Hum Gene Ther13:381–393 | Article | PubMed | ISI | ChemPort |

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.