Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis

Abstract

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1-3% of the world's population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS) studies showing that many psoriasis risk genes lie along the IL-23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. This review is focused on the IL-23/Th17 axis, providing an insight into key cell types, cytokines, and intracellular signaling pathways involved. This includes examination of currently available biological treatments, time to relapse post drug withdrawal, and rates of primary/secondary drug failure, showing the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely to reduce the burden of disease for the longest period possible.

Keywords: functional genomics; genetics; pathogenesis; psoriasis; tailored medicine.

Figure 1

A simplified diagram of the main psoriasis pathogenesis axis. Based on majority consensus in literature; the insulted keratinocyte releases self-DNA/RNA, forming a complex with the LL37 autoantigen, which then stimulates pDCs. IFNα released by pDCs alongside cytokines released from a variety of other cells activate mDCs to go on to stimulate the differentiation of naïve T cells and innate-like T cells into mature T Cells of varying function, which go on to propagate the psoriasis phenotype. Created with BioRender.com [33,66].