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Andrew Johnston,
Xianying Xing,
William R Swindell,
James Kochkodan,
Marybeth Riblett, Rajan P Nair,
Philip E Stuart,
Jun Ding,
John J Voorhees,
James T Elder,
Johann E Gudjonsson
[show abstract]
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ABSTRACT: The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology respectively, and genetic variation in this region significantly influences risk of psoriasis. Here we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expression of IL12B by monocytes and correlated with increased serum levels of IL-12, IFN-γ and the IFN-γ induced chemokine; CXCL10. In contrast, serum IL-23 levels were decreased in risk carriers compared to non-carriers. We further demonstrate that IL-12 is increased in psoriatic skin and that risk carriers manifest a skewing of the inflammatory network towards stronger IFN-γ responses. Taken together, our data demonstrate that the risk variant in IL12B associates with its increased expression, and predisposes to stronger Th1 polarization through deviation of the local inflammatory environment towards increased IL-12/IFN-γ at the expense of IL-23/IL-17 responses.
Human Molecular Genetics 01/2013; · 7.64 Impact Factor
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Lam C Tsoi,
Sarah L Spain,
Jo Knight,
Eva Ellinghaus,
Philip E Stuart,
Francesca Capon,
Jun Ding,
Yanming Li,
Trilokraj Tejasvi,
Johann E Gudjonsson, [......],
Matthew Waller,
Paul Weston,
Sara Widaa,
Pamela Whittaker, Rajan P Nair,
Andre Franke,
Jonathan N W N Barker,
Goncalo R Abecasis,
James T Elder,
Richard C Trembath
[show abstract]
[hide abstract]
ABSTRACT: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
Nature Genetics 11/2012; · 35.53 Impact Factor
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ABSTRACT: A single previous study has demonstrated significant association of psoriasis with copy number of β-defensin genes, using DNA from psoriasis cases and controls from Nijmegen and Erlangen. In this study, we attempted to replicate that finding in larger new cohorts from Erlangen (N=2,017) and Michigan (N=5,412), using improved methods for β-defensin copy number determination based on the paralog ratio test, and enhanced methods of analysis and association testing implemented in the CNVtools resource. We demonstrate that the association with psoriasis found in the discovery sample is maintained after applying improved typing and analysis methods (P=5.5 × 10(-4), odds ratio (OR)=1.25). We also find that the association is replicated in 2,616 cases and 2,526 controls from Michigan, although at reduced significance (P=0.014), but not in new samples from Erlangen (1,396 cases and 621 controls, P=0.38). Meta-analysis across all cohorts suggests a nominally significant association (P=6.6 × 10(-3)/2 × 10(-4)) with an effect size (OR=1.081) much lower than found in the discovery study (OR=1.32). This reduced effect size and significance on replication is consistent with a genuine but weak association.
Journal of Investigative Dermatology 06/2012; 132(10):2407-13. · 6.31 Impact Factor
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Catherine T Jordan,
Li Cao,
Elisha D O Roberson,
Shenghui Duan,
Cynthia A Helms, Rajan P Nair,
Kristina Callis Duffin,
Philip E Stuart,
David Goldgar,
Genki Hayashi, [......],
Michelle A Lowes,
Lynette Peddle,
Vinod Chandran,
Wilson Liao,
Proton Rahman,
Gerald G Krueger,
Dafna Gladman,
James T Elder,
Alan Menter,
Anne M Bowcock
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ABSTRACT: Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.
The American Journal of Human Genetics 04/2012; 90(5):796-808. · 10.60 Impact Factor
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David Ellinghaus,
Eva Ellinghaus, Rajan P Nair,
Philip E Stuart,
Tõnu Esko,
Andres Metspalu,
Sophie Debrus,
John V Raelson,
Trilokraj Tejasvi,
Majid Belouchi, [......],
Richard C Trembath,
Christopher G Mathew,
Gonçalo R Abecasis,
Stephan Weidinger,
Susanna Nikolaus,
Stefan Schreiber,
James T Elder,
Michael Weichenthal,
Michael Nothnagel,
Andre Franke
[show abstract]
[hide abstract]
ABSTRACT: Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53 × 10(-8), 11q13 near PRDX5, p(rs694739) = 3.71 × 10(-09), 22q11 at YDJC, p(rs181359) = 8.02 × 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99 × 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.
The American Journal of Human Genetics 04/2012; 90(4):636-47. · 10.60 Impact Factor
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ABSTRACT: The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments.
PLoS ONE 01/2012; 7(3):e34594. · 4.09 Impact Factor
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Eva Ellinghaus,
Philip E Stuart,
David Ellinghaus, Rajan P Nair,
Sophie Debrus,
John V Raelson,
Majid Belouchi,
Trilokraj Tejasvi,
Yanming Li,
Lam C Tsoi, [......],
Külli Kingo,
Christian Gieger,
H Erich Wichmann,
Ulrich Mrowietz,
Stephan Weidinger,
Stefan Schreiber,
Gonçalo R Abecasis,
James T Elder,
Michael Weichenthal,
Andre Franke
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ABSTRACT: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 single-nucleotide polymorphisms (SNPs) were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States, and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States, and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P=1.18 × 10(-8), odds ratio (OR)=1.27, 95% confidence interval (CI)=1.18-1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-κB family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3, and NFκBIA.
Journal of Investigative Dermatology 12/2011; 132(4):1133-40. · 6.31 Impact Factor
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[show abstract]
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ABSTRACT: The tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene has been associated with psoriasis, rheumatoid arthritis, type 1 diabetes mellitus, systemic lupus erythematosus, and celiac disease. TNFAIP3 encodes A20, a tumor necrosis factor (TNF)-α-inducible zinc finger protein thought to limit NF-κB-mediated immune responses. In this study, we report association of response of psoriasis to TNF blockers with two TNFAIP3 single-nucleotide polymorphisms (rs2230926 in exon 7 and rs610604 in intron 3) and their haplotypes. Treatment response was self-evaluated using a 0-5 visual analog scale in 433 psoriasis patients who received TNF blockers. Confirmation was sought in 199 psoriasis and psoriatic arthritis patients from Toronto who were followed up prospectively. Response variables were dichotomized separately in the two cohorts, yielding similar proportions of good responses. Whereas significant associations were observed only for the Michigan cohort, fixed-effects meta-analysis retained significant association between dosage of the G allele of rs610604 and good combined response to all TNF blockers (odds ratio (OR) = 1.50, P(corr) = 0.050) and etanercept (OR = 1.64, P(corr) = 0.016). The rs2230926 T-rs610604 G haplotype was similarly associated. By demonstrating an association with therapeutic response, these results provide a clinically relevant functional correlate to the recently described genetic association between psoriasis and TNFAIP3.
Journal of Investigative Dermatology 11/2011; 132(3 Pt 1):593-600. · 6.31 Impact Factor
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William R Swindell,
Andrew Johnston,
Steve Carbajal,
Gangwen Han,
Christian Wohn,
Jun Lu,
Xianying Xing, Rajan P Nair,
John J Voorhees,
James T Elder,
Xiao-Jing Wang,
Shigetoshi Sano,
Errol P Prens,
John DiGiovanni,
Mark R Pittelkow,
Nicole L Ward,
Johann E Gudjonsson
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ABSTRACT: Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.
PLoS ONE 01/2011; 6(4):e18266. · 4.09 Impact Factor
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Jun Ding,
Johann E Gudjonsson,
Liming Liang,
Philip E Stuart,
Yun Li,
Wei Chen,
Michael Weichenthal,
Eva Ellinghaus,
Andre Franke,
William Cookson, Rajan P Nair,
James T Elder,
Gonçalo R Abecasis
[show abstract]
[hide abstract]
ABSTRACT: Psoriasis, an immune-mediated, inflammatory disease of the skin and joints, provides an ideal system for expression quantitative trait locus (eQTL) analysis, because it has a strong genetic basis and disease-relevant tissue (skin) is readily accessible. To better understand the role of genetic variants regulating cutaneous gene expression, we identified 841 cis-acting eQTLs using RNA extracted from skin biopsies of 53 psoriatic individuals and 57 healthy controls. We found substantial overlap between cis-eQTLs of normal control, uninvolved psoriatic, and lesional psoriatic skin. Consistent with recent studies and with the idea that control of gene expression can mediate relationships between genetic variants and disease risk, we found that eQTL SNPs are more likely to be associated with psoriasis than are randomly selected SNPs. To explore the tissue specificity of these eQTLs and hence to quantify the benefits of studying eQTLs in different tissues, we developed a refined statistical method for estimating eQTL overlap and used it to compare skin eQTLs to a published panel of lymphoblastoid cell line (LCL) eQTLs. Our method accounts for the fact that most eQTL studies are likely to miss some true eQTLs as a result of power limitations and shows that ∼70% of cis-eQTLs in LCLs are shared with skin, as compared with the naive estimate of < 50% sharing. Our results provide a useful method for estimating the overlap between various eQTL studies and provide a catalog of cis-eQTLs in skin that can facilitate efforts to understand the functional impact of identified susceptibility variants on psoriasis and other skin traits.
The American Journal of Human Genetics 12/2010; 87(6):779-89. · 10.60 Impact Factor
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Eva Riveira-Munoz,
Su-Min He,
Georgia Escaram|[iacute]|s,
Philip E Stuart,
Ulrike H|[uuml]|ffmeier,
Catherine Lee,
Brian Kirby,
Akira Oka,
Emiliano Giardina,
Wilson Liao, [......],
Anne Bowcock,
Pui-Yan Kwok,
Giuseppe Novelli,
Hidetoshi Inoko,
Anthony W Ryan,
Richard C Trembath,
Andr|[eacute]| Reis,
Xue-Jun Zhang,
James T Elder,
Xavier Estivill
[show abstract]
[hide abstract]
ABSTRACT: A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OROverall=1.21 (1.15–1.27)), and for the first time directly demonstrates the deletion's association with psoriasis in the Chinese (OR=1.27 (1.16–1.34)) and Mongolian (OR=2.08 (1.44–2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.Abbreviations: LCE, late cornified envelope; LCE3C_LCE3B-del, deletion of LCE3C and LCE3B genes; OR, odds ratio; SNP, single-nucleotide polymorphism
Journal of Investigative Dermatology 11/2010; 131(5):1105-1109. · 6.31 Impact Factor
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Philip E Stuart, Rajan P Nair,
Eva Ellinghaus,
Jun Ding,
Trilokraj Tejasvi,
Johann E Gudjonsson,
Yun Li,
Stephan Weidinger,
Bernadette Eberlein,
Christian Gieger, [......],
Anne M Bowcock,
Ulrich Mrowietz,
Henry W Lim,
John J Voorhees,
Gonçalo R Abecasis,
Michael Weichenthal,
Andre Franke,
Proton Rahman,
Dafna D Gladman,
James T Elder
[show abstract]
[hide abstract]
ABSTRACT: We carried out a meta-analysis of two recent psoriasis genome-wide association studies with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 × 10⁻¹¹), one at FBXL19 (rs10782001, combined P = 9 × 10⁻¹⁰) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 × 10⁻⁸). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 × 10⁻⁵; rs10782001, combined P = 4 × 10⁻⁸; and rs12586317, combined P = 6 × 1⁻⁵) and purely cutaneous psoriasis (rs4795067, combined P = 1 × 10⁻⁸; rs10782001, combined P = 2 × 10⁻⁶; and rs12586317, combined P = 1 × 10⁻⁶). We also replicated a recently identified association signal near RNF114 (rs495337, combined P = 2 × 10⁻⁷).
Nature Genetics 11/2010; 42(11):1000-4. · 35.53 Impact Factor
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Liang-Dan Sun,
Hui Cheng,
Zai-Xing Wang,
An-Ping Zhang,
Pei-Guang Wang,
Jin-Hua Xu,
Qi-Xing Zhu,
Hai-Sheng Zhou,
Eva Ellinghaus,
Fu-Ren Zhang, [......],
Li-Mei Shao,
Jian-Lan Liu,
Feng-Yu Zhang,
Wei-Dong Du,
Andre Franke,
Anne M Bowcock,
James T Elder,
Jian-Jun Liu,
Sen Yang,
Xue-Jun Zhang
[show abstract]
[hide abstract]
ABSTRACT: We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10⁻⁸) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⁻²¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⁻³ and P = 7.9 × 10⁻³, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⁻³ and P = 1.5 × 10⁻³, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.
Nature Genetics 11/2010; 42(11):1005-9. · 35.53 Impact Factor
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Eva Ellinghaus,
David Ellinghaus,
Philip E Stuart, Rajan P Nair,
Sophie Debrus,
John V Raelson,
Majid Belouchi,
Hélène Fournier,
Claudia Reinhard,
Jun Ding, [......],
Tom H Karlsen,
Gabriele Mayr,
Mario Albrecht,
Dieter Kabelitz,
Ulrich Mrowietz,
Gonçalo R Abecasis,
James T Elder,
Stefan Schreiber,
Michael Weichenthal,
Andre Franke
[show abstract]
[hide abstract]
ABSTRACT: Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-wide association analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with follow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from three independent replication panels. We identified an association at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two additional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36 × 10⁻¹⁰ for rs13210247 and combined P = 1.24 × 10⁻¹⁶ for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57 × 10⁻¹² for rs33980500) suggested that TRAF3IP2 represents a shared susceptibility for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-κB transcription factor family.
Nature Genetics 11/2010; 42(11):991-5. · 35.53 Impact Factor
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Eva Riveira-Munoz,
Su-Min He,
Georgia Escaramís,
Philip E Stuart,
Ulrike Hüffmeier,
Catherine Lee,
Brian Kirby,
Akira Oka,
Emiliano Giardina,
Wilson Liao, [......],
Anne Bowcock,
Pui-Yan Kwok,
Giuseppe Novelli,
Hidetoshi Inoko,
Anthony W Ryan,
Richard C Trembath,
André Reis,
Xue-Jun Zhang,
James T Elder,
Xavier Estivill
[show abstract]
[hide abstract]
ABSTRACT: A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OR(Overall) = 1.21 (1.15-1.27)), and for the first time directly demonstrates the deletion's association with psoriasis in the Chinese (OR = 1.27 (1.16-1.34)) and Mongolian (OR = 2.08 (1.44-2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.
Journal of Investigative Dermatology 11/2010; 131(5):1105-9. · 6.31 Impact Factor
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Johann E Gudjonsson,
Andrew Johnston,
Stefan W Stoll,
Mary B Riblett,
Xianying Xing,
James J Kochkodan,
Jun Ding, Rajan P Nair,
Abhishek Aphale,
John J Voorhees,
James T Elder
[show abstract]
[hide abstract]
ABSTRACT: The Wnt gene family encodes a set of highly conserved secreted signaling proteins that have major roles in embryogenesis and tissue homeostasis. Yet the expression of this family of important mediators in psoriasis, a disease characterized by marked changes in keratinocyte growth and differentiation, is incompletely understood. We subjected 58 paired biopsies from lesional and uninvolved psoriatic skin and 64 biopsies from normal skin to global gene expression profiling. WNT5A transcripts were upregulated fivefold in lesional skin, accompanied by increased Wnt-5a protein levels. Notably, WNT5A mRNA was markedly induced by IL-1alpha, tumor necrosis factor-alpha, IFN-gamma, and transforming growth factor-alpha in cultured keratinocytes. Frizzled 2 (FZD2) and FZD5, which encode receptors for Wnt5A, were also increased in lesional psoriatic skin. In contrast, expression of WIF1 mRNA, encoding a secreted antagonist of the Wnt proteins, was downregulated >10-fold in lesional skin, along with decreased WNT inhibitory factor (WIF)-1 immunostaining. Interestingly, pathway analysis along with reduced AXIN2 expression and lack of nuclear translocation of beta-catenin indicated a suppression of canonical Wnt signaling in lesional skin. The results of our study suggest a shift away from canonical Wnt signaling toward noncanonical pathways driven by interactions between Wnt-5a and its cognate receptors in psoriasis, accompanied by impaired homeostatic inhibition of Wnt signaling by WIF-1 and dickkopf.
Journal of Investigative Dermatology 04/2010; 130(7):1849-59. · 6.31 Impact Factor
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[show abstract]
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ABSTRACT: To further elucidate molecular alterations in psoriasis, we performed a gene expression study of 58 paired lesional and uninvolved psoriatic and 64 control skin samples. Comparison of involved psoriatic (PP) and normal (NN) skin identified 1,326 differentially regulated transcripts encoding 918 unique genes (549 up- and 369 downregulated), of which over 600 are to our knowledge previously unreported, including S100A7A, THRSP, and ELOVL3. Strongly upregulated genes included SERPINB4, PI3, DEFB4, and several S100-family members. Strongly downregulated genes included Wnt-inhibitory factor-1 (WIF1), beta-cellulin (BTC), and CCL27. Enriched gene ontology categories included immune response, defense response, and keratinocyte differentiation. Biological processes regulating fatty acid and lipid metabolism were enriched in the down-regulated gene set. Comparison of the psoriatic transcriptome to the transcriptomes of cytokine-stimulated cultured keratinocytes (IL-17, IL-22, IL-1alpha, IFN-gamma, TNF-alpha, and OSM) showed surprisingly little overlap, with the cytokine-stimulated keratinocyte expression representing only 2.5, 0.7, 1.5, 5.6, 5.0, and 1.9% of the lesional psoriatic dysregulated transcriptome, respectively. This comprehensive analysis of differentially regulated transcripts in psoriasis provides additional insight into the pathogenic mechanisms involved and emphasizes the need for more complex yet tractable experimental models of psoriasis.
Journal of Investigative Dermatology 03/2010; 130(7):1829-40. · 6.31 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Psoriasis is a common and debilitating disease of the skin, nails, and joints, with an acknowledged but complex genetic basis. Early genome-wide linkage studies of psoriasis focused on segregation of microsatellite markers in families; however, the only locus consistently identified resided in the major histocompatibility complex. Subsequently, several groups mapped this locus to the vicinity of HLA-C, and two groups have reported HLA-Cw6 itself to be the major susceptibility allele. More recently, the development of millions of single-nucleotide polymorphisms, coupled with the development of high-throughput genotyping platforms and a comprehensive map of human haplotypes, has made possible a genome-wide association approach using cases and controls rather than families. Taking advantage of these developments, we participated in a collaborative genome-wide association study of psoriasis involving thousands of cases and controls. Initial analysis of these data revealed and/or confirmed association between psoriasis and seven genetic loci-HLA-C, IL12B, IL23R, IL23A, IL4/IL13, TNFAIP3, and TNIP1-and ongoing studies are revealing additional loci. Here, we review the epidemiology, immunopathology, and genetics of psoriasis, and present a disease model integrating its genetics and immunology.
Journal of Investigative Dermatology 10/2009; 130(5):1213-26. · 6.31 Impact Factor
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Bing-Jian Feng,
Liang-Dan Sun,
Razieh Soltani-Arabshahi,
Anne M Bowcock, Rajan P Nair,
Philip Stuart,
James T Elder,
Steven J Schrodi,
Ann B Begovich,
Gonçalo R Abecasis,
Xue-Jun Zhang,
Kristina P Callis-Duffin,
Gerald G Krueger,
David E Goldgar
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ABSTRACT: Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 10(-6), OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3 x 10(-47), 6 x 10(-8), and 3 x 10(-7), respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.
PLoS Genetics 09/2009; 5(8):e1000606. · 8.69 Impact Factor
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Johann E Gudjonsson,
Jun Ding,
Xing Li, Rajan P Nair,
Trilokraj Tejasvi,
Zhaohui S Qin,
Debashis Ghosh,
Abhishek Aphale,
Deborah L Gumucio,
John J Voorhees,
Goncalo R Abecasis,
James T Elder
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ABSTRACT: Psoriasis is a genetically determined inflammatory skin disease. Although the transition from uninvolved into lesional skin is accompanied by changes in the expression of multiple genes, much less is known about the difference between uninvolved skin from psoriatic patients as opposed to skin from normal individuals. Multiple biochemical and morphological changes were reported decades ago in uninvolved psoriatic skin but remain poorly understood. Here, we show dysregulation of 223 transcripts representing 179 unique genes in uninvolved psoriatic skin, 178 of which were not previously known to be altered in their expression. The proteins encoded by these transcripts are involved in lipid metabolism, antimicrobial defenses, epidermal differentiation, and control of cutaneous vasculature. Cluster analysis of transcripts with significantly altered expression identified a group of genes involved in lipid metabolism with highly correlated gene expression. Promoter analysis showed enrichment for binding sites of three transcription factors; peroxisome proliferator-activator receptor alpha (PPARA), sterol regulatory element-binding protein (SREBF), and estrogen receptor 2 (ESR2), suggesting that the coordinate regulation of lipid metabolic genes may be related to the action of these factors. Taken together, our results identify a "pre-psoriatic" gene expression signature, suggesting decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.
Journal of Investigative Dermatology 08/2009; 129(12):2795-804. · 6.31 Impact Factor
