This is a complex inflammatory disease of the skin that affects as many as 7.5 million Americans (2-3% of the population). Between 10 and 30 percent of PS patients develop psoriatic arthritis (PsA). Both PS and PsA are serious conditions for which there are no cures, and warranting sophisticated medical care and therapies. Total direct and indirect health care costs of PS patients are ~ $11.25 billion annually. PS can cause as much disability as other major diseases, including diabetes, heart disease, hypertension and depression accompanied by thoughts of suicide. It goes hand-in-hand with conditions such as Crohn's disease, diabetes, metabolic syndrome, obesity, hypertension, heart attack, cardiovascular disease and liver disease. Despite progress in understanding altered cellular pathways and genetic risk factors of PS, it is still poorly understood. Current treatments present a challenge for patients and their health care providers because no one treatment works for everyone, some treatments lose effectiveness over time, many treatments used are in combination with other treatments, and all treatments may cause a unique set of side effects.

Enhanced keratinocyte proliferation, disrupted terminal differentiation and infiltration of immune cells are characteristics of the disease. A cross section of normal skin (left) contrasts greatly with the thickened skin of a psoriasis lesion, which exhibits the characteristic disorganized cornified envelope (barrier) at the cell surface.

In psoriasis, genetic risk factors and environmental trigger contribute to the "rewiring" of the circuitry of the transcriptome of the skin. We previously performed a global analysis of the psoriasis transcriptome and identified over 1300 differentially expressed genes in involved (lesional) versus normal skin (Bowcock et al.,2001; Zhou et al., 2003)

Left panel: Difference between normal and psoriasis/involved skin (same magnification) showing hyper-proliferative epidermis and inflammatory cell infiltrate.

Right panel: Venn Diagram representing the overlapping and non-overlapping expression alteration among the 3 skin groups (normal, psoriasis/involved and psoriasis/uninvolved) described by Zhou et al., 2003. The diagram shows the number of genes (number of up-regulated genes/number of down-regulated genes) with the indicated expression patterns.

      Approaches we are using to understand psoriasis pathogenesis include Genetic Analysis:

This is being performed with linkage analysis in multiply affected families (Tomfohrde et al., 1994) and genome wide association studies (Liu et al., 2008; Nair et al., 2009). We are currently replicating previous associations and performing follow-up studies on associated regions. One such region lies downstream of the COG1 gene on chromosome 13.

Since GWAS cannot account for more than about 25% of the genetic contribution to psoriasis we are also performing copy number variant detection in patients. We recently described a common deletion within the epidermal differentiation complex associated with psorasis, (de Cid et al., 2009). We are also following up additional CNVs detected in our GWAS, doing additional screens for structural variation in patients and performing complete resequencing of the exomes and genomes of psoriasis and psoriatic arthritis sufferers.

Washington University School of Medicine, Department of Genetics, Division of Human Genetics
Last updated Aug. 26, 2009