Genomewide Scan Reveals Association of Psoriasis with IL-23 and NF-κB Pathways

Nair, Rajan P.; Duffin, Kristina Callis; Helms, Cindy; Ding, Jin-Jun; Stuart, Philip E; Goldgar, David E; Gudjonsson, Johann E; Li, Yun; Tejasvi, Trilokraj; Feng, Bing-Jian; Ruether, Andreas; Schreiber, Stefan; Weichenthal, Michael; Gladman, Dafna D.; Rahman, Proton; Schrodi, Steven J.; Prahalad, Sampath; Guthery, Stephen L.; Fischer, Judith; Liao, Wilson; Kwok, Pui-Yan; Menter, Alan; Lathrop, G Mark; Wise, Carol A; Begovich, Ann B; Voorhees, John J.; Elder, James T; Krueger, Gerald G; Bowcock, Anne M; Abecasis, Gonçalo R

doi:10.1038/ng.311

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Genomewide Scan Reveals Association of Psoriasis with IL-23 and NF-κB Pathways

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Author(s): Rajan P. Nair ¹ , Kristina Callis Duffin ² , Cindy Helms ³ , Jun Ding ⁴ , Philip E. Stuart ¹ , David Goldgar ² , Johann E. Gudjonsson ¹ , Yun Li ⁴ , Trilokraj Tejasvi ¹ , Bing Jian Feng ² , Andreas Ruether ⁵ , Stefan Schreiber ⁵ , Michael Weichenthal ⁶ , Dafna Gladman ⁷ , Proton Rahman ⁸ , Steven J. Schrodi ⁹ , Sampath Prahalad ¹⁰ , Stephen L Guthery ¹⁰ , Judith Fischer ¹¹ , Wilson Liao ¹² , Pui-Yan Kwok ¹² , Alan Menter ¹³ , G. Mark Lathrop ¹¹ , Carol A. Wise ¹⁴ , Ann B. Begovich ⁹ , John J. Voorhees ¹ , James T. Elder ¹ ^, ¹⁵ ^, ^# , Gerald G. Krueger ² ^, ^# , Anne M. Bowcock ³ ^, ^# , Gonçalo R. Abecasis ⁴ ^, ^#

Publication date (Electronic): 25 January 2009

Journal: Nature genetics

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Abstract

Psoriasis is a common immune mediated disorder that affects the skin, nails, and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 European ancestry psoriasis cases and 1,436 controls. Twenty-one promising SNPs were followed-up in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with p < 5×10 ⁻⁸ overall). Loci with confirmed association encode HLA-C, three genes involved in IL-23 signaling ( IL23A, IL23R, IL12B), two genes that act downstream of TNF-α and regulate NF-κB signaling ( TNIP1, TNFAIP3), and two genes involved in the modulation of Th2 immune responses ( IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

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Most cited references 21

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Pathogenesis and therapy of psoriasis.

Michelle Lowes, Anne M Bowcock, James G. Krueger (2007)

Psoriasis is one of the most common human skin diseases and is considered to have key genetic underpinnings. It is characterized by excessive growth and aberrant differentiation of keratinocytes, but is fully reversible with appropriate therapy. The trigger of the keratinocyte response is thought to be activation of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and chemokines implicated in pathogenesis. The newest therapies for psoriasis target its immune components and may predict potential treatments for other inflammatory human diseases.

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T(H)-17 cells in the circle of immunity and autoimmunity.

Estelle Bettelli, Mohamed Oukka, Vijay K. Kuchroo (2007)

CD4(+) effector T cells have been categorized into two subsets: T helper type 1 (T(H)1) and T(H)2. Another subset of T cells that produce interleukin 17 (IL-17; 'T(H)-17 cells') has been identified that is highly proinflammatory and induces severe autoimmunity. Whereas IL-23 serves to expand previously differentiated T(H)-17 cell populations, IL-6 and transforming growth factor-beta (TGF-beta) induce the differentiation of T(H)-17 cells from naive precursors. These data suggest a dichotomy between CD4(+) regulatory T cells positive for the transcription factor Foxp3 and T(H)-17 cells: TGF-beta induces Foxp3 and generates induced regulatory T cells, whereas IL-6 inhibits TGF-beta-driven Foxp3 expression and together with TGF-beta induces T(H)-17 cells. Emerging data regarding T(H)-17 cells suggest a very important function for this T cell subset in immunity and disease.

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Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.

Miles Parkes, Jeffrey Barrett, Natalie Prescott … (2007)

A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

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Author and article information

Contributors

: On behalf of : for the Collaborative Association Study of Psoriasis

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 17 December 2008

Publication date (Electronic): 25 January 2009

Publication date (Print): February 2009

Publication date PMC-release: 16 September 2009

Volume: 41

Issue: 2

Pages: 199-204

Affiliations

[1 ]Department of Dermatology, University of Michigan, Ann Arbor, MI

[2 ]Department of Dermatology, University of Utah, Salt Lake City, UT

[3 ]Division of Human Genetics, Department of Genetics, Washington University at St. Louis, St. Louis, MO

[4 ]Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI

[5 ]Institute for Clinical Molecular Biology, University of Kiel, Kiel, Germany

[6 ]Department of Dermatology, University of Kiel, Kiel, Germany

[7 ]Department of Rheumatology, University of Toronto, Toronto, Ontario

[8 ]Department of Medicine, Memorial University, St. John’s, Newfoundland

[9 ]Celera, 1401 Harbor Bay Parkway, Alameda, CA

[10 ]Departments of Pediatrics, Rheumatology and Gastroenterology, University of Utah, Salt Lake City, UT

[11 ]Centre National de Génotypage, Institut Génomique, Commissariat à l’Énergie Atomique, Evry, France

[12 ]Department of Dermatology, University of California, San Francisco

[13 ]Department of Dermatology, Baylor University Medical Center, Dallas, TX

[14 ]Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX

[15 ]Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI

[16 ]A list of important contributors to the Collaborative Association Study of Psoriasis is included at the back of the manuscript.

Author notes

[# ]These authors conceived and co-directed the project. Correspondence can be addressed to them at jelder@ 123456umich.edu , gerald.krueger@ 123456hsc.utah.edu , bowcock@ 123456wustl.edu or goncalo@ 123456umich.edu

[*]

These authors contributed equally and are joint first authors.

Article

Manuscript ID: nihpa83342

DOI: 10.1038/ng.311

PMC ID: 2745122

PubMed ID: 19169254

SO-VID: 28b4a4a0-f073-4528-b602-06c379a21fd7