Genetic factors play an important role in psoriatic arthritis (PsA) and psoriasis vulgaris (PsV). The overall goal of this proposal is to identify the genetic determinant(s) within the MHC that predispose to PsA. Very recently, we identified a 9.7 kb indel located between HLA-B and HLA-C. Our preliminary data support the hypothesis that the MHC component of PsA and PsV arose on an """"""""ancestral risk chromosome"""""""" lacking the 9.7 kb indel segment. Our data are consistent with two models: one in which the HLA-B and HLA-C alleles on this chromosome each confer risk for PsA and PsV (two-determinant model), and one in which a single feature of this chromosome located between HLA-B and C is involved in the genesis of PsA and PsV (one-determinant model). The former model would be consistent with the idea that the ancestral chromosome provided particularly effective protection against a pathogen due to the participation of both HLA-B and HLA-C. The latter model would be more consistent with a regulatory sequence. We have the experimental tools to test these models. However, our PsA phenotype is currently based only on the presence of joint complaints, and not on objective findings of PsA. We have identified a large resource of PsA patients, and a co-investigator with outstanding expertise in the clinical evaluation of PsA. Therefore, to create a genetic resource for PsA, and to provide critical tests for the hypothesis outlined above, we propose the following specific aims: 1. To accurately phenotype joint and skin involvement, to collect blood samples, and to prepare immortalized lymphoblastoid cell lines and DNA from (a) 400 patients with PsA and (b) 400 individuals who have had PsV for at least 5 years without developing PsA. Also, (c) to collect blood samples and to prepare immortalized lymphoblastoid cell lines and DNA from 400 individuals with no history of PsV or PsA. 2. To define the evolutionary history of the ancestral risk chromosome, and to distinguish between the one- and two-determinant risk models, by comparative DNA sequencing across the HLA-B-C interval. 3. To type 40 microsatellites and 40 SNPs across an interval extending from TNFB to STG in the individuals ascertained in Aim 1, to generate and cluster haplotypes in order to identify ancestral chromosomes, to determine the HLA-B and HLA-C alleles carried on each ancestral chromosome, to assess these chromosomes for risk of PsA by case-control association testing, and to sequence any ancestral chromosome segments conferring risk for PsA that have not already been sequenced in Aim 2.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GMA-1 (01))
Program Officer
Moshell, Alan N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
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
Budu-Aggrey, Ashley; Bowes, John; Stuart, Philip E et al. (2017) A rare coding allele in IFIH1 is protective for psoriatic arthritis. Ann Rheum Dis 76:1321-1324
Jadon, Deepak R; Sengupta, Raj; Nightingale, Alison et al. (2017) Serum bone-turnover biomarkers are associated with the occurrence of peripheral and axial arthritis in psoriatic disease: a prospective cross-sectional comparative study. Arthritis Res Ther 19:210
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
Ellinghaus, David; Jostins, Luke; Spain, Sarah L et al. (2016) Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 48:510-8
Das, Sayantan; Stuart, Philip E; Ding, Jun et al. (2015) Fine mapping of eight psoriasis susceptibility loci. Eur J Hum Genet 23:844-53
Tsoi, Lam C; Elder, James T; Abecasis, Goncalo R (2015) Graphical algorithm for integration of genetic and biological data: proof of principle using psoriasis as a model. Bioinformatics 31:1243-9
Stuart, Philip E; Nair, Rajan P; Tsoi, Lam C et al. (2015) Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture. Am J Hum Genet 97:816-36

Showing the most recent 10 out of 49 publications