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 #
5R01AR054966-02
Application #
7470568
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Baker, Carl
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$632,351
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
Tsoi, Lam C; Yang, Jingjing; Liang, Yun et al. (2018) Transcriptional determinants of individualized inflammatory responses at anatomically separate sites. J Allergy Clin Immunol 141:805-808
Tsoi, Lam C; Patrick, Matthew T; Elder, James T (2018) Research Techniques Made Simple: Using Genome-Wide Association Studies to Understand Complex Cutaneous Disorders. J Invest Dermatol 138:e23-e29
Yu, Ning; Lambert, Sylviane; Bornstein, Joshua et al. (2018) The Act1 D10N missense variant impairs CD40 signaling in human B-cells. Genes Immun :
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
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
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
Hermann, Helen; Runnel, Toomas; Aab, Alar et al. (2017) miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis. J Invest Dermatol 137:1945-1954
Dand, Nick; Mucha, Sören; Tsoi, Lam C et al. (2017) Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling. Hum Mol Genet 26:4301-4313
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
Prins, Bram P; Abbasi, Ali; Wong, Anson et al. (2016) Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. PLoS Med 13:e1001976

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