Psoriasis is a chronic inflammatory skin condition that affects 0.11%-1.58% of people globally. There are multiple types of psoriasis, of which plaque psoriasis is the most common, affecting up to 80% of individuals with psoriasis. Other types of psoriasis include guttate, pustular, flexural, erythrodermic, and follicular. Psoriasis can significantly impair a person's quality of life and lead to serious comorbidities such as psoriatic arthritis, hypertension, cardiovascular diseases, and diabetes.
Psoriasis is most often caused by overactivity of cytokines in the immune system. Cytokines, including interleukin (IL)-17, IL-22, IL-23, and tumor necrosis factor alpha, are associated with an increased risk for psoriasis. These cytokines lead to persistent inflammation, leading to uncontrolled keratinocyte proliferation, which causes the skin manifestations characteristic of psoriasis. However, the exact cause of this disruption is still not clear.
The etiopathogenesis of psoriasis is complex, with genetic, immunologic, and environmental factors thought to play a key role in disease development. The risk for psoriasis is higher among first- and second-degree relatives of people with psoriasis, suggesting a genetic association with disease development. Indeed, studies have reported that monozygotic have a two to three times higher risk for psoriasis compared with dizygotic twins. Moreover, the heritability of psoriasis is more than 60% even though the disease involves multiple susceptibility genetic loci.
Initial genetic studies for psoriasis included familial linkage analysis. These analyses identified nine different regions or loci known as psoriasis susceptibility (PSORS)1-9 that contribute to disease susceptibility. PSORS1 is the major determinant of psoriasis susceptibility, whereas PSORS2 and PSORS4 have weaker linkages.
The PSORS1 locus maps to the major histocompatibility complex (MHC) on chromosome 6p21. Fine mapping studies defined the locus as encompassing nine genes, three of which (HLA-C, CCHCR1, and CDSN) are significantly associated with psoriasis. HLA-C encodes an MHC class I receptor that takes part in psoriasis-related immune responses by presenting antigens to CD8+ T lymphocytes. Serologic studies have further identified that the HLA-Cw6 allele plays a key role in the pathogenesis of psoriasis by binding to one or more psoriasis autoantigens.
The PSORS2 locus maps to chromosome 17q25, as observed in a single large family (PS1) of European ancestry. Sequencing of DNA from members of this family identified mutations within the caspase recruitment domain family, member 14 (CARD14), indicating its association with the risk for psoriasis. CARD14 encodes an adaptor protein which is expressed in keratinocytes where it mediates TRAF2-dependent nuclear factor-kappa B (NF-kappa B) signal transduction. The NF-kappa B pathway encodes several genes involved in intracellular signaling and is one of the key factors in innate immune responses. Overall, CARD14 mutations lead to NF-kappa B activation, which eventually causes the production of pro-inflammatory cytokines characteristic of psoriasis.
The PSORS4 locus maps to chromosome 1q21, spanning the epidermal differentiation complex (EDC). This region comprises more than 60 genes involved in terminal keratinocyte differentiation. Deletion of LCE3B and LCE3C, two EDC genes that are associated with skin barrier function, is implicated in the risk for psoriasis.
Following the completion of the Human Genome Project in 2003, advances in technology led to study of the entire genome instead of single genes or isolated variants. Genome-wide association studies (GWASs) analyzed several million single nucleotide polymorphisms (SNP)s, or genetic markers, indicating slight differences in allele frequencies between patients with psoriasis and healthy individuals. The first psoriasis GWAS, took place in 2007, after which different targeted genotypic platforms were developed, including the Exome chip (Twist Bioscience) and Immunochip (Illumina). The Exome chip involved markers mapping to coding regions, and the Immunochip helped in analyzing SNPs previously associated with immune-mediated disorders. Together, these platforms identified 63 psoriasis susceptibility loci that can increase the risk of developing psoriasis.