Psoriasis is a common, immune-mediated, inflammatory and hyperproliferative disease of the skin and joints. Conclusive evidence demonstrates psoriasis has a genetic basis. We have recently identified HLA-Cw6 as the disease allele at PSORS1, the major MHC-linked component of psoriasis susceptibility. However, only about 10% of HLA-Cw6 carriers develop psoriasis, implying that additional genes must contribute as well. Published and preliminary data provide evidence for replication of linkage or association at several non-MHC loci. However, no non-MHC susceptibility genes have been conclusively identified to date. Association studies have the potential to identify these genes, provided that a sufficiently density of SNPs is studied in a large sample, and that positive results are followed up by appropriate replication and fine-mapping studies. Identification of these non-MHC genes is the first overall goal of this proposal. The skin is a uniquely accessible organ and the major target of the immune system in psoriasis, resulting in many changes in gene expression. Prior linkage studies of gene expression in immortalized cell lines have identified important genetic elements responsible for controlling gene expression. The second, and related, overall goal of this project is to build a gene-expression map in psoriatic skin, characterizing gene expression profiles in uninvolved and diseased skin from affected individuals as well as normal skin from control individuals. In addition to identifying genes that are differentially expressed, we will relate gene expression profiles in skin to specific genetic loci, and where possible, DNA variants. To accomplish these goals, we propose to carry out the following specific aims: 1. Collect skin biopsies and blood samples from 300 early onset psoriatic cases and 300 controls, and prepare RNA and DNA, respectively, from these samples. 2. Perform whole-genome association analysis on 600 early-onset psoriatic cases and 600 controls utilizing DNA microarrays capable of assaying ~500,000 single nucleotide polymorphisms (SNPs). 3. Perform global gene expression analysis on the 300 cases and 300 controls collected in Aim 1, and analyze these data conjointly with the genome-wide SNP data obtained in Aim 2. 4. Follow-up 6,000 SNPs in a replication cohort of 900 cases and 900 controls, and compare our data with that derived from an independent whole-genome association scan of psoriasis in Germany. Refine the candidate associations by performing dense SNP genotyping in confirmed regions of association. Quantify the effect of each SNP on gene expression, probabilistically infer the state of ungenotyped SNPs, quantify their effects on transcript levels, and organize a publicly accessible database. Identification of the remaining psoriasis susceptibility genes will elucidate the molecular basis of this enigmatic disease, and identify targets for more specific and effective therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054966-05
Application #
8101831
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Cibotti, Ricardo
Project Start
2007-07-15
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$597,764
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Lambert, Sylviane; Swindell, William R; Tsoi, Lam C et al. (2017) Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses. J Invest Dermatol 137:1501-1511
Mehta, Nehal N; Teague, Heather L; Swindell, William R et al. (2017) IFN-? and TNF-? synergism may provide a link between psoriasis and inflammatory atherogenesis. Sci Rep 7:13831
Tsoi, Lam C; Stuart, Philip E; Tian, Chao et al. (2017) Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat Commun 8:15382
Niehues, Hanna; Tsoi, Lam C; van der Krieken, Danique A et al. (2017) Psoriasis-Associated Late Cornified Envelope (LCE) Proteins Have Antibacterial Activity. J Invest Dermatol 137:2380-2388
Rittié, Laure; Tejasvi, Trilokraj; Harms, Paul W et al. (2016) Sebaceous Gland Atrophy in Psoriasis: An Explanation for Psoriatic Alopecia? J Invest Dermatol 136:1792-800
Tsoi, Lam C; Iyer, Matthew K; Stuart, Philip E et al. (2015) Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin. Genome Biol 16:24
Swindell, William R; Sarkar, Mrinal K; Stuart, Philip E et al. (2015) Psoriasis drug development and GWAS interpretation through in silico analysis of transcription factor binding sites. Clin Transl Med 4:13
Koch, Manja; Baurecht, Hansjörg; Ried, Janina S et al. (2015) Psoriasis and cardiometabolic traits: modest association but distinct genetic architectures. J Invest Dermatol 135:1283-1293
Baurecht, Hansjörg; Hotze, Melanie; Brand, Stephan et al. (2015) Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. Am J Hum Genet 96:104-20
Stuart, Philip E; Tejasvi, Trilokraj; Shaiq, Pakeeza A et al. (2015) A single SNP surrogate for genotyping HLA-C*06:02 in diverse populations. J Invest Dermatol 135:1177-1180

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