- Psoriasis is a complex disease that affects approximately 2% of the population. It results in abnormal proliferation of immature keratinocytes and recruitment of T cells to the dermis and epidermis. This results in three major features: induration, scaling, and erythema. A variety of novel proteins have been identified in psoriatic skin that include pro-inflammatory cytokines, adhesion molecules, HLA-DR, keratins, and alteration in the cellular distribution of integrins. The mode of inheritance of psoriasis is complex, although a familial component is now accepted as a result of twin studies, sib pair studies, the identification of large numbers of multiply affected families, and more recently, by evidence for linkage to particular chromosomal regions in some families. The applicants previously provided strong evidence for linkage to the distal end of chromosome 17q. HOMOG estimates indicated that the disease is genetically heterogeneous. A second study recently showed evidence for linkage of psoriasis to chromosome 4 (near D4S1535) in five families from Ireland. In both of these studies, psoriasis susceptibility behaves as an autosomal dominant trait with high penetrance. There is also an autoimmune component to psoriasis, and Cw6 carriers are at 15-fold higher risk of disease. The applicants now propose to localize additional genes conferring susceptibility to psoriasis by performing a genome-wide linkage screen on 250 sib pairs and 27 multiply affected families. Markers will be selected at 3 cM intervals, and genotyping will be performed using an ABI 377. This will require the generation of 1,300,000 genotypes over 3 years (approximately 450,000 per year). Susceptibility loci will be identified by parametric and nonparametric means with GENEHUNTER. Regions where p<0.01 will be analyzed further by collaborators in an additional 250 sib pairs. The applicants will refine potential susceptibility regions with closely linked markers. The results of this study should be the localization of additional psoriasis susceptibility genes to defined regions of the genome. In the last year of funding any highly promising candidate genes in these regions will be screened for alterations in affected individuals from linked families and in sporadic cases. When alterations are found, they will be screened for in 100 unrelated controls to determine the possibility of their contributing to the development of psoriasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044577-05
Application #
6328845
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
1998-01-01
Project End
2002-01-31
Budget Start
2000-12-01
Budget End
2002-01-31
Support Year
5
Fiscal Year
2001
Total Cost
$369,700
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Williams, Fionnuala; Meenagh, Ashley; Sleator, Carole et al. (2005) Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis. Hum Immunol 66:836-41
Helms, Cynthia; Saccone, Nancy L; Cao, Li et al. (2005) Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR. Hum Genet 118:466-76
Bowcock, Anne M; Cookson, William O C M (2004) The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum Mol Genet 13 Spec No 1:R43-55
Speckman, Rebecca A; Wright Daw, Jil A; Helms, Cynthia et al. (2003) Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum Genet 112:34-41
International Psoriasis Genetics Consortium (2003) The International Psoriasis Genetics Study: assessing linkage to 14 candidate susceptibility loci in a cohort of 942 affected sib pairs. Am J Hum Genet 73:430-7
Moran, J L; Johnston, S H; Rauskolb, C et al. (1999) Genomic structure, mapping, and expression analysis of the mammalian Lunatic, Manic, and Radical fringe genes. Mamm Genome 10:535-41
Bhalerao, J; Bowcock, A M (1998) The genetics of psoriasis: a complex disorder of the skin and immune system. Hum Mol Genet 7:1537-45