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Psoriasis: HELP
Articles by John J. Voorhees
Based on 38 articles published since 2008
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Between 2008 and 2019, J. J. Voorhees wrote the following 38 articles about Psoriasis.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Molecular dissection of psoriasis: integrating genetics and biology. 2010

Elder, James T / Bruce, Allen T / Gudjonsson, Johann E / Johnston, Andrew / Stuart, Philip E / Tejasvi, Trilokraj / Voorhees, John J / Abecasis, Gonçalo R / Nair, Rajan P. ·Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA. jelder@umich.edu ·J Invest Dermatol · Pubmed #19812592.

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.

2 Clinical Trial Modulation of epidermal transcription circuits in psoriasis: new links between inflammation and hyperproliferation. 2013

Swindell, William R / Johnston, Andrew / Xing, Xianying / Voorhees, John J / Elder, James T / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America. ·PLoS One · Pubmed #24260178.

ABSTRACT: BACKGROUND: Whole-genome expression profiling has been used to characterize molecular-level differences between psoriasis lesions and normal skin. Pathway analysis, however, is complicated by the fact that expression profiles have been derived from bulk skin biopsies with RNA derived from multiple cell types. RESULTS: We analyzed gene expression across a large sample of psoriatic (PP) and uninvolved/normal (PN) skin biopsies (n = 215 patients). We identified 1975 differentially expressed genes, including 8 associated with psoriasis susceptibility loci. To facilitate pathway analysis, PP versus PN differences in gene expression were analyzed with respect to 235 gene modules, each containing genes with a similar expression pattern in keratinocytes and epidermis. We identified 30 differentially expressed modules (DEMs) biased towards PP-increased or PP-decreased expression. These DEMs were associated with regulatory axes involving cytokines (e.g., IFN-γ, IL-17A, TNF-α), transcription factors (e.g., STAT1, NF-κB, E2F, RUNX1) and chromatin modifiers (SETDB1). We identified an interferon-induced DEM with genes encoding anti-viral proteins (designated "STAT1-57"), which was activated in psoriatic epidermis but repressed following biologic therapy. Genes within this DEM shared a motif near the transcription start site resembling the interferon-stimulated response element (ISRE). CONCLUSIONS: We analyzed a large patient cohort and developed a new approach for delineating epidermis-specific pathways and regulatory mechanisms that underlie altered gene expression in psoriasis. Our findings highlight previously unrecognized "transcription circuits" that can provide targets for development of non-systemic therapies.

3 Article Genetic signature to provide robust risk assessment of psoriatic arthritis development in psoriasis patients. 2018

Patrick, Matthew T / Stuart, Philip E / Raja, Kalpana / Gudjonsson, Johann E / Tejasvi, Trilokraj / Yang, Jingjing / Chandran, Vinod / Das, Sayantan / Callis-Duffin, Kristina / Ellinghaus, Eva / Enerbäck, Charlotta / Esko, Tõnu / Franke, Andre / Kang, Hyun M / Krueger, Gerald G / Lim, Henry W / Rahman, Proton / Rosen, Cheryl F / Weidinger, Stephan / Weichenthal, Michael / Wen, Xiaoquan / Voorhees, John J / Abecasis, Gonçalo R / Gladman, Dafna D / Nair, Rajan P / Elder, James T / Tsoi, Lam C. ·Department of Dermatology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA. · Morgridge Institute for Research, Madison, 53715, WI, USA. · Ann Arbor Veterans Affairs Hospital, Ann Arbor, 48105, MI, USA. · Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA. · Department of Human Genetics, Emory University School of Medicine, Atlanta, 30322, GA, USA. · Department of Medicine, Division of Rheumatology, University of Toronto, Toronto, Ontario, M5G 2C4, Canada. · Centre for Prognosis Studies in the Rheumatic Diseases, Krembil Research Institute, University of Toronto, Toronto, Ontario, M5T 2S8, Canada. · Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. · Department of Dermatology, University of Utah, Salt Lake City, Utah, 84132, USA. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, 24105, Germany. · Department of Dermatology, Linköping University, Linköping, SE-581 83, Sweden. · Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia. · Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA. · Department of Dermatology, Henry Ford Hospital, Detroit, 48202, MI, USA. · Memorial University, St. John's, Newfoundland and Labrador, A1B 3X9, Canada. · Division of Dermatology, Toronto Western Hospital, University of Toronto, Toronto, M5G 2C4, Ontario, Canada. · Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, 24105, Germany. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA. alextsoi@med.umich.edu. · Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA. alextsoi@med.umich.edu. · Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, 4810, MI, USA. alextsoi@med.umich.edu. ·Nat Commun · Pubmed #30301895.

ABSTRACT: Psoriatic arthritis (PsA) is a complex chronic musculoskeletal condition that occurs in ~30% of psoriasis patients. Currently, no systematic strategy is available that utilizes the differences in genetic architecture between PsA and cutaneous-only psoriasis (PsC) to assess PsA risk before symptoms appear. Here, we introduce a computational pipeline for predicting PsA among psoriasis patients using data from six cohorts with >7000 genotyped PsA and PsC patients. We identify 9 new loci for psoriasis or its subtypes and achieve 0.82 area under the receiver operator curve in distinguishing PsA vs. PsC when using 200 genetic markers. Among the top 5% of our PsA prediction we achieve >90% precision with 100% specificity and 16% recall for predicting PsA among psoriatic patients, using conditional inference forest or shrinkage discriminant analysis. Combining statistical and machine-learning techniques, we show that the underlying genetic differences between psoriasis subtypes can be used for individualized subtype risk assessment.

4 Article Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling. 2017

Dand, Nick / Mucha, Sören / Tsoi, Lam C / Mahil, Satveer K / Stuart, Philip E / Arnold, Andreas / Baurecht, Hansjörg / Burden, A David / Callis Duffin, Kristina / Chandran, Vinod / Curtis, Charles J / Das, Sayantan / Ellinghaus, David / Ellinghaus, Eva / Enerback, Charlotta / Esko, Tõnu / Gladman, Dafna D / Griffiths, Christopher E M / Gudjonsson, Johann E / Hoffman, Per / Homuth, Georg / Hüffmeier, Ulrike / Krueger, Gerald G / Laudes, Matthias / Lee, Sang Hyuck / Lieb, Wolfgang / Lim, Henry W / Löhr, Sabine / Mrowietz, Ulrich / Müller-Nurayid, Martina / Nöthen, Markus / Peters, Annette / Rahman, Proton / Reis, André / Reynolds, Nick J / Rodriguez, Elke / Schmidt, Carsten O / Spain, Sarah L / Strauch, Konstantin / Tejasvi, Trilokraj / Voorhees, John J / Warren, Richard B / Weichenthal, Michael / Weidinger, Stephan / Zawistowski, Matthew / Nair, Rajan P / Capon, Francesca / Smith, Catherine H / Trembath, Richard C / Abecasis, Goncalo R / Elder, James T / Franke, Andre / Simpson, Michael A / Barker, Jonathan N. ·Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. · Department of Dermatology. · Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA. · St John's Institute of Dermatology, Faculty of Life Sciences & Medicine, King's College London, London, UK. · Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany. · Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. · Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, UK. · Department of Dermatology, University of Utah, Salt Lake City, UT, USA. · Department of Medicine. · Department of Laboratory Medicine and Pathobiology. · Institute of Medical Science, University of Toronto, Toronto, ON, Canada. · Krembil Research Institute, University Health Network, Toronto, ON, Canada. · NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK. · Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. · Division of Cell Biology and Dermatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. · Estonian Biobank, Estonian Genome Center, University of Tartu, Tartu, Estonia. · Dermatology Centre, Salford Royal Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. · Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland. · Institute of Human Genetics, University of Bonn, Bonn, Germany. · Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. · Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. · I. Department of Medicine. · Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany. · Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA. · Institute of Genetic Epidemiology, Helmholtz Zentrum Munich, Neuherberg, Germany. · Memorial University of Newfoundland, St. John's, NL, Canada. · Dermatological Sciences, Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK. · Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. · Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany. · Dermatology Centre, Salford Road NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. · Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. · Ann Arbor Veterans Hospital, Ann Arbor, MI, USA. ·Hum Mol Genet · Pubmed #28973304.

ABSTRACT: Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

5 Article Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. 2017

Tsoi, Lam C / Stuart, Philip E / Tian, Chao / Gudjonsson, Johann E / Das, Sayantan / Zawistowski, Matthew / Ellinghaus, Eva / Barker, Jonathan N / Chandran, Vinod / Dand, Nick / Duffin, Kristina Callis / Enerbäck, Charlotta / Esko, Tõnu / Franke, Andre / Gladman, Dafna D / Hoffmann, Per / Kingo, Külli / Kõks, Sulev / Krueger, Gerald G / Lim, Henry W / Metspalu, Andres / Mrowietz, Ulrich / Mucha, Sören / Rahman, Proton / Reis, Andre / Tejasvi, Trilokraj / Trembath, Richard / Voorhees, John J / Weidinger, Stephan / Weichenthal, Michael / Wen, Xiaoquan / Eriksson, Nicholas / Kang, Hyun M / Hinds, David A / Nair, Rajan P / Abecasis, Gonçalo R / Elder, James T. ·Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. · Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Computational Medicine &Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. · 23andMe, Inc., Mountain View, California 94041, USA. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany. · St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK. · Department of Medicine, Division of Rheumatology, University of Toronto, Toronto, Ontario, Canada M5S 1A8. · Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada M5T 2S8. · Department of Dermatology, University of Utah, Salt Lake City, Utah 84132, USA. · Department of Dermatology, Linköping University, Linköping SE-581 83, Sweden. · Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. · Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. · Institute of Human Genetics, University of Bonn, Bonn 53127, Germany. · Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel 4031, Switzerland. · Dermatology Clinic, Tartu University Hospital, Department of Dermatology and Venereology, University of Tartu, Tartu 50417, Estonia. · Department of Pathophysiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu, Tartu 50411, Estonia. · Department of Reproductive Biology, Estonian University of Life Sciences, Tartu 51006, Estonia. · Department of Dermatology, Henry Ford Hospital, Detroit, Michigan 48202, USA. · Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany. · Memorial University, St. John's, Newfoundland, Newfoundland and Labrador, Canada A1B 3X9. · Institute of Human Genetics, FAU Erlangen-Nürnberg, Erlangen 91054, Germany. · Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan 48105, USA. · Department of Medical and Molecular Genetics, King's College London, London WC2R 2LS, UK. ·Nat Commun · Pubmed #28537254.

ABSTRACT: Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8

6 Article Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation. 2017

Sarkar, Mrinal K / Kaplan, Nihal / Tsoi, Lam C / Xing, Xianying / Liang, Yun / Swindell, William R / Hoover, Paul / Aravind, Maya / Baida, Gleb / Clark, Matthew / Voorhees, John J / Nair, Rajan P / Elder, James T / Budunova, Irina / Getsios, Spiro / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. · Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: johanng@med.umich.edu. ·J Invest Dermatol · Pubmed #28259685.

ABSTRACT: The factors involved in maintaining a localized inflammatory state in psoriatic skin remain poorly understood. Here, we demonstrate through metabolomic and transcriptomic profiling marked suppression of glucocorticoid biosynthesis in the epidermis of psoriatic skin leading to localized deficiency of cortisol. Utilizing a 3D human epidermis model, we demonstrate that glucocorticoid biosynthesis is suppressed by proinflammatory cytokines and that glucocorticoid deficiency promotes inflammatory responses in keratinocytes. Finally, we show in vitro and in vivo that treatment with topical glucocorticoids leads to rapid restoration of glucocorticoid biosynthesis gene expression coincident with normalization of epidermal differentiation and suppression of inflammatory responses. Taken together, our data suggest that localized glucocorticoid deficiency in psoriatic skin interferes with epidermal differentiation and promotes a sustained and localized inflammatory response. This may shed new light on the mechanism of action of topical steroids, and demonstrates the critical role of endogenous steroid in maintaining both inflammatory and differentiation homeostasis in the epidermis.

7 Article Six-transmembrane epithelial antigens of the prostate comprise a novel inflammatory nexus in patients with pustular skin disorders. 2017

Liang, Yun / Xing, Xianying / Beamer, Maria A / Swindell, William R / Sarkar, Mrinal K / Roberts, Liza Wolterink / Voorhees, John J / Kahlenberg, J Michelle / Harms, Paul W / Johnston, Andrew / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan, Ann Arbor, Mich. · Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio. · Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Mich. · Department of Dermatology, University of Michigan, Ann Arbor, Mich; Department of Pathology, University of Michigan, Ann Arbor, Mich. · Department of Dermatology, University of Michigan, Ann Arbor, Mich. Electronic address: johanng@med.umich.edu. ·J Allergy Clin Immunol · Pubmed #27884600.

ABSTRACT: BACKGROUND: Pustular skin disorders are a category of difficult-to-treat and potentially life-threatening conditions that involve the appearance of neutrophil-rich pustules. The molecular basis of most pustular skin conditions has remained unknown. OBJECTIVE: We sought to investigate the molecular basis of 3 pustular skin disorders: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), and acute generalized exanthematous pustulosis (AGEP). METHODS: Microarray analyses were performed to profile genome-wide gene expression of skin biopsy specimens obtained from patients with GPP, PPP, or AGEP and healthy control subjects. Functional enrichment, gene network, and k-means clustering analyses were used to identify molecular pathways dysregulated in patients with these disorders. Immunohistochemistry and immunofluorescence were used to determine protein localization. Quantitative RT-PCR and ELISA were used to determine transcript and secreted cytokine levels. Small interfering RNA was used to decrease transcript levels. RESULTS: Molecules and pathways related to neutrophil chemotaxis emerged as common alterations in patients with GPP, PPP, and AGEP, which is consistent with the pustular phenotypes. Expression of two 6-transmembrane epithelial antigens of the prostate (STEAP) proteins, STEAP1 and STEAP4, was increased in patients' skin and colocalized with IL-36γ around neutrophilic pustules. STEAP1/4 expression clustered with and positively correlated with that of IL-1, the IL-36 family proteins, and CXCL1/8. STEAP4 expression was activated by cytokines and suppressed by inhibition of mitogen-activated protein kinase kinase 1/2, whereas STEAP1 expression appeared less prone to such dynamic regulation. Importantly, STEAP1/4 knockdown resulted in impaired induction of a broad spectrum of proinflammatory cytokines, including IL-1, IL-36, and the neutrophil chemotaxins CXCL1 and CXCL8. STEAP1/4 knockdown also reduced the ability of keratinocytes to induce neutrophil chemotaxis. CONCLUSION: Transcriptomic changes in 3 pustular skin disorders, GPP, PPP, and AGEP, converged on neutrophil chemotaxis and diapedesis and cytokines known to drive neutrophil-rich inflammatory processes, including IL-1 and members of the IL-36 family. STEAP1 and STEAP4 positively regulate the induction of proinflammatory neutrophil-activating cytokines.

8 Article IL-17 Responses Are the Dominant Inflammatory Signal Linking Inverse, Erythrodermic, and Chronic Plaque Psoriasis. 2016

Xing, Xianying / Liang, Yun / Sarkar, Mrinal K / Wolterink, Liza / Swindell, William R / Voorhees, John J / Harms, Paul W / Kahlenberg, Joanne M / Johnston, Andrew / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. · Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: johanng@med.umich.edu. ·J Invest Dermatol · Pubmed #27448749.

ABSTRACT: -- No abstract --

9 Article Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture. 2015

Stuart, Philip E / Nair, Rajan P / Tsoi, Lam C / Tejasvi, Trilokraj / Das, Sayantan / Kang, Hyun Min / Ellinghaus, Eva / Chandran, Vinod / Callis-Duffin, Kristina / Ike, Robert / Li, Yanming / Wen, Xiaoquan / Enerbäck, Charlotta / Gudjonsson, Johann E / Kõks, Sulev / Kingo, Külli / Esko, Tõnu / Mrowietz, Ulrich / Reis, Andre / Wichmann, H Erich / Gieger, Christian / Hoffmann, Per / Nöthen, Markus M / Winkelmann, Juliane / Kunz, Manfred / Moreta, Elvia G / Mease, Philip J / Ritchlin, Christopher T / Bowcock, Anne M / Krueger, Gerald G / Lim, Henry W / Weidinger, Stephan / Weichenthal, Michael / Voorhees, John J / Rahman, Proton / Gregersen, Peter K / Franke, Andre / Gladman, Dafna D / Abecasis, Gonçalo R / Elder, James T. ·Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA. · Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany. · Department of Medicine, Division of Rheumatology, University of Toronto, Toronto, ON M5T 2S8, Canada; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada. · Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA. · Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. · Department of Clinical and Experimental Medicine, Division of Cell Biology and Dermatology, Linköping University, 581 83 Linköping, Sweden. · Department of Pathophysiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu, 50411 Tartu, Estonia; Department of Reproductive Biology, Estonian University of Life Sciences, 51014 Tartu, Estonia. · Dermatology Clinic, Tartu University Hospital, Department of Dermatology and Venereology, University of Tartu, 50417 Tartu, Estonia. · Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia. · Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. · Institute of Human Genetics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany. · Institute of Epidemiology I, Helmholtz Zentrum Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, 81377 Munich, Germany; Institute of Medical Statistics and Epidemiology, Technical University Munich, 80333 Munich, Germany. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. · Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany. · Neurologische Klinik and Poliklinik, Klinikum rechts der Isar, Technische Universität München, 80333 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany. · Department of Dermatology, Venereology and Allergology, University of Leipzig, 04103 Leipzig, Germany. · Saint Paul Rheumatology, Eagan, MN 55121, USA. · Seattle Rheumatology Associates, 601 Broadway, Suite 600, Seattle, WA 98122, USA. · Allergy, Immunology, and Rheumatology Division, University of Rochester Medical Center, Rochester, NY 14623, USA. · National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK. · Department of Dermatology, Henry Ford Hospital, Detroit, MI 48202, USA. · Memorial University, St. John's, NL A1C 5B8, Canada. · The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA. Electronic address: jelder@umich.edu. ·Am J Hum Genet · Pubmed #26626624.

ABSTRACT: Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

10 Article Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci. 2015

Tsoi, Lam C / Spain, Sarah L / Ellinghaus, Eva / Stuart, Philip E / Capon, Francesca / Knight, Jo / Tejasvi, Trilokraj / Kang, Hyun M / Allen, Michael H / Lambert, Sylviane / Stoll, Stefan W / Weidinger, Stephan / Gudjonsson, Johann E / Koks, Sulev / Kingo, Külli / Esko, Tonu / Das, Sayantan / Metspalu, Andres / Weichenthal, Michael / Enerback, Charlotta / Krueger, Gerald G / Voorhees, John J / Chandran, Vinod / Rosen, Cheryl F / Rahman, Proton / Gladman, Dafna D / Reis, Andre / Nair, Rajan P / Franke, Andre / Barker, Jonathan N W N / Abecasis, Goncalo R / Trembath, Richard C / Elder, James T. ·Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Division of Genetics and Molecular Medicine, King's College London, London WC2R 2LS, UK. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Neuroscience Research, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8. · National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK. · Department of Dermatology, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, 24105 Kiel, Germany. · Department of Pathophysiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu, 50409 Tartu, Estonia. · Department of Dermatology and Venereology, University of Tartu, 50409 Tartu, Estonia. · Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia. · Department of Dermatology, Linköping University, SE-581 83 Linköping, Sweden. · Department of Dermatology, University of Utah, Salt Lake City, Utah 84132, USA. · Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8. · Department of Medicine, Division of Dermatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8. · Department of Medicine, Memorial University, St John's, Newfoundland, Canada A1C 5B8. · Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen 91054, Germany. · Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, UK. · Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan 48105, USA. ·Nat Commun · Pubmed #25939698.

ABSTRACT: Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.

11 Article Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin. 2015

Tsoi, Lam C / Iyer, Matthew K / Stuart, Philip E / Swindell, William R / Gudjonsson, Johann E / Tejasvi, Trilokraj / Sarkar, Mrinal K / Li, Bingshan / Ding, Jun / Voorhees, John J / Kang, Hyun M / Nair, Rajan P / Chinnaiyan, Arul M / Abecasis, Goncalo R / Elder, James T. · ·Genome Biol · Pubmed #25723451.

ABSTRACT: BACKGROUND: Although analysis pipelines have been developed to use RNA-seq to identify long non-coding RNAs (lncRNAs), inference of their biological and pathological relevance remains a challenge. As a result, most transcriptome studies of autoimmune disease have only assessed protein-coding transcripts. RESULTS: We used RNA-seq data from 99 lesional psoriatic, 27 uninvolved psoriatic, and 90 normal skin biopsies, and applied computational approaches to identify and characterize expressed lncRNAs. We detect 2,942 previously annotated and 1,080 novel lncRNAs which are expected to be skin specific. Notably, over 40% of the novel lncRNAs are differentially expressed and the proportions of differentially expressed transcripts among protein-coding mRNAs and previously-annotated lncRNAs are lower in psoriasis lesions versus uninvolved or normal skin. We find that many lncRNAs, in particular those that are differentially expressed, are co-expressed with genes involved in immune related functions, and that novel lncRNAs are enriched for localization in the epidermal differentiation complex. We also identify distinct tissue-specific expression patterns and epigenetic profiles for novel lncRNAs, some of which are shown to be regulated by cytokine treatment in cultured human keratinocytes. CONCLUSIONS: Together, our results implicate many lncRNAs in the immunopathogenesis of psoriasis, and our results provide a resource for lncRNA studies in other autoimmune diseases.

12 Article Fine mapping of eight psoriasis susceptibility loci. 2015

Das, Sayantan / Stuart, Philip E / Ding, Jun / Tejasvi, Trilokraj / Li, Yanming / Tsoi, Lam C / Chandran, Vinod / Fischer, Judith / Helms, Cynthia / Duffin, Kristina Callis / Voorhees, John J / Bowcock, Anne M / Krueger, Gerald G / Lathrop, G Mark / Nair, Rajan P / Rahman, Proton / Abecasis, Goncalo R / Gladman, Dafna / Elder, James T. ·Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA. · Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. · 1] Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA [2] Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON, Canada. · Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, Evry, France. · National Heart and Lung Institute, Imperial College London, London, UK. · Department of Dermatology, University of Utah, Salt Lake City, UT, USA. · Department of Medicine, Memorial University, St John's, NL, Canada. · 1] Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON, Canada [2] Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, Toronto, ON, Canada. · 1] Department of Dermatology, University of Michigan, Ann Arbor, MI, USA [2] Ann-Arbor Veteran Affairs Hospital, Ann Arbor, MI, USA. ·Eur J Hum Genet · Pubmed #25182136.

ABSTRACT: Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49 239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 × 10(-74)), rs6924962 (P = 3.21 × 10(-19)) and rs892666 (P = 1.11 × 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 × 10(-16)) and rs918518 (P = 3.22 × 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 × 10(-13)), IL13 (rs1295685; P = 1.65 × 10(-7)), IL23A (rs61937678; P = 1.82 × 10(-7)) and TNFAIP3 (rs642627; P = 5.90 × 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.

13 Article Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. 2014

Okada, Yukinori / Han, Buhm / Tsoi, Lam C / Stuart, Philip E / Ellinghaus, Eva / Tejasvi, Trilokraj / Chandran, Vinod / Pellett, Fawnda / Pollock, Remy / Bowcock, Anne M / Krueger, Gerald G / Weichenthal, Michael / Voorhees, John J / Rahman, Proton / Gregersen, Peter K / Franke, Andre / Nair, Rajan P / Abecasis, Gonçalo R / Gladman, Dafna D / Elder, James T / de Bakker, Paul I W / Raychaudhuri, Soumya. ·Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-0085, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA. · Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. · Institute of Clinical Molecular Biology, Kiel University, Kiel 24105, Germany. · Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON M5T 2S8, Canada; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada. · Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada. · National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK. · Department of Dermatology, University of Utah, Salt Lake City, UT 84112, USA. · Department of Dermatology, Christian-Albrechts-Universität zu Kiel, Kiel 24105, Germany. · Memorial University of Newfoundland, St. John's, NL A1C5S7, Canada. · The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA. · Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON M5T 2S8, Canada; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada; Toronto Western Research Institute, University of Toronto, Toronto, ON M5G 2M9, Canada. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA. · Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands. Electronic address: pdebakker@umcutrecht.nl. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester M13 9PT, UK. Electronic address: soumya@broadinstitute.org. ·Am J Hum Genet · Pubmed #25087609.

ABSTRACT: Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.

14 Article Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era. 2014

Swindell, William R / Stuart, Philip E / Sarkar, Mrinal K / Voorhees, John J / Elder, James T / Johnston, Andrew / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, MI 48109-2200, USA. wswindel@umich.edu. ·BMC Med Genomics · Pubmed #24885462.

ABSTRACT: BACKGROUND: Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings. METHODS: We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding. RESULTS: Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4. CONCLUSIONS: These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci.

15 Article Integrative RNA-seq and microarray data analysis reveals GC content and gene length biases in the psoriasis transcriptome. 2014

Swindell, William R / Xing, Xianying / Voorhees, John J / Elder, James T / Johnston, Andrew / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan wswindel@umich.edu. · Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan. ·Physiol Genomics · Pubmed #24844236.

ABSTRACT: Gene expression profiling of psoriasis has driven research advances and may soon provide the basis for clinical applications. For expression profiling studies, RNA-seq is now a competitive technology, but RNA-seq results may differ from those obtained by microarray. We therefore compared findings obtained by RNA-seq with those from eight microarray studies of psoriasis. RNA-seq and microarray datasets identified similar numbers of differentially expressed genes (DEGs), with certain genes uniquely identified by each technology. Correspondence between platforms and the balance of increased to decreased DEGs was influenced by mRNA abundance, GC content, and gene length. Weakly expressed genes, genes with low GC content, and long genes were all biased toward decreased expression in psoriasis lesions. The strength of these trends differed among array datasets, most likely due to variations in RNA quality. Gene length bias was by far the strongest trend and was evident in all datasets regardless of the expression profiling technology. The effect was due to differences between lesional and uninvolved skin with respect to the genome-wide correlation between gene length and gene expression, which was consistently more negative in psoriasis lesions. These findings demonstrate the complementary nature of RNA-seq and microarray technology and show that integrative analysis of both data types can provide a richer view of the transcriptome than strict reliance on a single method alone. Our results also highlight factors affecting correspondence between technologies, and we have established that gene length is a major determinant of differential expression in psoriasis lesions.

16 Article Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms. 2014

Li, Bingshan / Tsoi, Lam C / Swindell, William R / Gudjonsson, Johann E / Tejasvi, Trilokraj / Johnston, Andrew / Ding, Jun / Stuart, Philip E / Xing, Xianying / Kochkodan, James J / Voorhees, John J / Kang, Hyun M / Nair, Rajan P / Abecasis, Goncalo R / Elder, James T. ·Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. · Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, USA. · Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA; Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA. · Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: goncalo@umich.edu. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: jelder@umich.edu. ·J Invest Dermatol · Pubmed #24441097.

ABSTRACT: To increase our understanding of psoriasis, we used high-throughput complementary DNA sequencing (RNA-seq) to assay the transcriptomes of lesional psoriatic and normal skin. We sequenced polyadenylated RNA-derived complementary DNAs from 92 psoriatic and 82 normal punch biopsies, generating an average of ∼38 million single-end 80-bp reads per sample. Comparison of 42 samples examined by both RNA-seq and microarray revealed marked differences in sensitivity, with transcripts identified only by RNA-seq having much lower expression than those also identified by microarray. RNA-seq identified many more differentially expressed transcripts enriched in immune system processes. Weighted gene coexpression network analysis (WGCNA) revealed multiple modules of coordinately expressed epidermal differentiation genes, overlapping significantly with genes regulated by the long noncoding RNA TINCR, its target gene, staufen-1 (STAU1), the p63 target gene ZNF750, and its target KLF4. Other coordinately expressed modules were enriched for lymphoid and/or myeloid signature transcripts and genes induced by IL-17 in keratinocytes. Dermally expressed genes were significantly downregulated in psoriatic biopsies, most likely because of expansion of the epidermal compartment. These results show the power of WGCNA to elucidate gene regulatory circuits in psoriasis, and emphasize the influence of tissue architecture in both differential expression and coexpression analysis.

17 Article Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients. 2013

Swindell, William R / Johnston, Andrew / Voorhees, John J / Elder, James T / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, MI 48109-2200, USA. wswindel@umich.edu ·BMC Genomics · Pubmed #23915137.

ABSTRACT: BACKGROUND: Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample. RESULTS: We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-γ-strong signature, with increased expression of genes induced by IFN-γ in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders. CONCLUSIONS: Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.

18 Article Genetic associations of psoriasis in a Pakistani population. 2013

Shaiq, P A / Stuart, P E / Latif, A / Schmotzer, C / Kazmi, A H / Khan, M S / Azam, M / Tejasvi, T / Voorhees, J J / Raja, G K / Elder, J T / Qamar, R / Nair, R P. ·PMAS-Arid Agriculture University Rawalpindi, Rawalpindi, Pakistan. ·Br J Dermatol · Pubmed #23495851.

ABSTRACT: BACKGROUND: Genetic predisposition to psoriasis, an inflammatory skin disease affecting 0·2-4% of the world population, is well established. Thus far, 41 psoriasis susceptibility loci reach genome-wide significance (P ≤ 5 × 10(-8) ). Identification of genetic susceptibility loci in diverse populations will help understand the underlying biology of psoriasis susceptibility. OBJECTIVES: The primary objective of this study was to examine psoriasis susceptibility associations previously reported in Chinese and caucasian populations in a Pakistani cohort. METHODS: Blood samples and phenotype data were collected from psoriasis cases and controls in Islamabad, Pakistan. DNA was isolated and genotypes of selected susceptibility markers were determined. The data were analysed using χ(2) tests or logistic regression for psoriasis association. RESULTS: HLA-Cw6 showed the strongest association [odds ratio (OR) 2·43, P = 2·3 × 10(-12) ]. HLA-Cw1 showed marginally significant association (OR 1·66, P = 0·049), suggesting that the HLA-Cw1-B46 risk haplotype may be present in the Pakistani population. Three other loci (IL4/IL13, NOS2, TRAF3IP2) showed nominally significant association (P < 0·05). CONCLUSIONS: HLA-Cw6 is strongly associated with psoriasis susceptibility in the Pakistani population, as has been found in every other population studied. In addition, HLA-Cw1 showed marginal association, reflecting the relative geographical proximity and thus likely genetic relatedness to other populations in which the HLA-Cw1-B46 haplotype is known to be associated. A larger cohort and a denser marker set will be required for further analysis of psoriasis associations in the South Asian population.

19 Article Susceptibility-associated genetic variation at IL12B enhances Th1 polarization in psoriasis. 2013

Johnston, Andrew / Xing, Xianying / Swindell, William R / Kochkodan, James / Riblett, Marybeth / Nair, Rajan P / Stuart, Philip E / Ding, Jun / Voorhees, John J / Elder, James T / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA. ·Hum Mol Genet · Pubmed #23376980.

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 when compared with non-carriers. We further demonstrate that IL-12 is increased in psoriatic skin and that risk carriers manifest a skewing of the inflammatory network toward 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 toward increased IL-12/IFN-γ at the expense of IL-23/IL-17 responses.

20 Article Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. 2012

Tsoi, Lam C / Spain, Sarah L / Knight, Jo / Ellinghaus, Eva / Stuart, Philip E / Capon, Francesca / Ding, Jun / Li, Yanming / Tejasvi, Trilokraj / Gudjonsson, Johann E / Kang, Hyun M / Allen, Michael H / McManus, Ross / Novelli, Giuseppe / Samuelsson, Lena / Schalkwijk, Joost / Ståhle, Mona / Burden, A David / Smith, Catherine H / Cork, Michael J / Estivill, Xavier / Bowcock, Anne M / Krueger, Gerald G / Weger, Wolfgang / Worthington, Jane / Tazi-Ahnini, Rachid / Nestle, Frank O / Hayday, Adrian / Hoffmann, Per / Winkelmann, Juliane / Wijmenga, Cisca / Langford, Cordelia / Edkins, Sarah / Andrews, Robert / Blackburn, Hannah / Strange, Amy / Band, Gavin / Pearson, Richard D / Vukcevic, Damjan / Spencer, Chris C A / Deloukas, Panos / Mrowietz, Ulrich / Schreiber, Stefan / Weidinger, Stephan / Koks, Sulev / Kingo, Külli / Esko, Tonu / Metspalu, Andres / Lim, Henry W / Voorhees, John J / Weichenthal, Michael / Wichmann, H Erich / Chandran, Vinod / Rosen, Cheryl F / Rahman, Proton / Gladman, Dafna D / Griffiths, Christopher E M / Reis, Andre / Kere, Juha / Anonymous6390741 / Anonymous6400741 / Anonymous6410741 / Anonymous6420741 / Nair, Rajan P / Franke, Andre / Barker, Jonathan N W N / Abecasis, Goncalo R / Elder, James T / Trembath, Richard C. ·Department of Biostatistics, Center for Statistical Genetics, University of Michigan Ann Arbor, MI, USA. ·Nat Genet · Pubmed #23143594.

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.

21 Article Heterogeneity of inflammatory and cytokine networks in chronic plaque psoriasis. 2012

Swindell, William R / Xing, Xianying / Stuart, Philip E / Chen, Cynthia S / Aphale, Abhishek / Nair, Rajan P / Voorhees, John J / Elder, James T / Johnston, Andrew / Gudjonsson, Johann E. ·Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #22479649.

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.

22 Article Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin (IL)-19, IL-20 and IL-24. 2012

Wang, F / Smith, N / Maier, L / Xia, W / Hammerberg, C / Chubb, H / Chen, C / Riblett, M / Johnston, A / Gudjonsson, J E / Helfrich, Y / Kang, S / Fisher, G J / Voorhees, J J. ·Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA. frawang@med.umich.edu ·Br J Dermatol · Pubmed #22458549.

ABSTRACT: BACKGROUND: Psoriasis is a Th17/Th1-mediated skin disease that often responds to antitumour necrosis factor (TNF)-α therapies, such as etanercept. OBJECTIVES: To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis. METHODS: We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder patients prior to substantial clinical improvement (≤ 4 weeks). RESULTS: By 1 week, etanercept acutely suppressed gene expression of the interleukin (IL)-20 subfamily of cytokines (IL-19, IL-20, IL-24), which were found to be predominantly epidermis-derived and which are implicated in stimulating epidermal hyperplasia. Additionally, by 1 week of therapy, suppression of other keratinocyte-derived products (chemokines, antimicrobial proteins) occurred, while suppression of epidermal regenerative hyperplasia occurred within 1-3 weeks. Th17 elements (IL-23p19, IL-12p40, IL-17A, IL-22) were suppressed by 3-4 weeks. In vitro, TNF-α and IL-17A coordinately stimulated the expression of the IL-20 subfamily in normal keratinocytes. CONCLUSIONS: Based on the rapid suppression of regenerative hyperplasia, chemokines and other keratinocyte-derived products, including the IL-20 subfamily, we propose that epidermal activation is a very early target of etanercept. As many of these keratinocyte markers are stimulated by TNF-α, their rapid downregulation is likely to reflect etanercept's antagonism of TNF-α. Additionally, decreased epidermal hyperplasia might result specifically from acute suppression of the IL-20 subfamily, which is also a likely consequence of etanercept's antagonism of TNF-α. Thus, the IL-20 subfamily has potential importance in the pathogenesis of psoriasis and therapeutic response to etanercept.

23 Article TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis. 2012

Tejasvi, Trilokraj / Stuart, Philip E / Chandran, Vinod / Voorhees, John J / Gladman, Dafna D / Rahman, Proton / Elder, James T / Nair, Rajan P. ·Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5675, USA. ·J Invest Dermatol · Pubmed #22113471.

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.

24 Article Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis. 2011

Swindell, William R / Johnston, Andrew / Carbajal, Steve / Han, Gangwen / Wohn, Christian / Lu, Jun / Xing, Xianying / Nair, Rajan P / Voorhees, John J / Elder, James T / Wang, Xiao-Jing / Sano, Shigetoshi / Prens, Errol P / DiGiovanni, John / Pittelkow, Mark R / Ward, Nicole L / Gudjonsson, Johann E. ·Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America. wswindell@genetics.med.harvard.edu ·PLoS One · Pubmed #21483750.

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.

25 Article IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. 2011

Johnston, Andrew / Xing, Xianying / Guzman, Andrew M / Riblett, MaryBeth / Loyd, Candace M / Ward, Nicole L / Wohn, Christian / Prens, Errol P / Wang, Frank / Maier, Lisa E / Kang, Sewon / Voorhees, John J / Elder, James T / Gudjonsson, Johann E. ·Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA. ·J Immunol · Pubmed #21242515.

ABSTRACT: IL-1F6, IL-1F8, and IL-1F9 and the IL-1R6(RP2) receptor antagonist IL-1F5 constitute a novel IL-1 signaling system that is poorly characterized in skin. To further characterize these cytokines in healthy and inflamed skin, we studied their expression in healthy control, uninvolved psoriasis, and psoriasis plaque skin using quantitative RT-PCR and immunohistochemistry. Expression of IL-1F5, -1F6, -1F8, and -1F9 were increased 2 to 3 orders of magnitude in psoriasis plaque versus uninvolved psoriasis skin, which was supported immunohistologically. Moreover, treatment of psoriasis with etanercept led to significantly decreased IL-1F5, -1F6, -1F8, and -1F9 mRNAs, concomitant with clinical improvement. Similarly increased expression of IL-1F5, -1F6, -1F8, and -1F9 was seen in the involved skin of two mouse models of psoriasis. Suggestive of their importance in inflamed epithelia, IL-1α and TNF-α induced IL-1F5, -1F6, -1F8, and -1F9 transcript expression by normal human keratinocytes. Microarray analysis revealed that these cytokines induce the expression of antimicrobial peptides and matrix metalloproteinases by reconstituted human epidermis. In particular, IL-1F8 increased mRNA expression of human β-defensin (HBD)-2, HBD-3, and CAMP and protein secretion of HBD-2 and HBD-3. Collectively, our data suggest important roles for these novel cytokines in inflammatory skin diseases and identify these peptides as potential targets for antipsoriatic therapies.

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