# Soriasis and Seasonality: Exploring the Genetic and Epigenetic Interactions
## 3 Molecular Background of Psoriasis  
### Genetics of Psoriasis  
Psoriasis vulgaris is a multifactorial disorder in which the genetic background has a major impact on the course of the symptoms [18]. About 10 to 40 percent of PsV patients are also affected by psoriatic arthritis [6; 17]. PsV and PsA share strong hereditary components. Genes responsible for symptoms may be inherited dominantly or recessively [19]. PsA occurs at a high rate in close relatives, more likely in mono-compared dizygotic twins [20]. Genome-wide association studies (GWAS) revealed more than eighty loci associated with psoriasis, including IL-23/NF-kB/epidermal differentiation signaling [19]. Genes associated with PsA include _HLA-B/C_, _HLA-B_, _IL-12B_, _IL-23R_, _TNP1_, _TRAF3 IP3_, and _REL_[19; 21]. These genes are associated with the maintenance of cutaneous barrier functioning, control of innate immune responses mediated by the nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), and interferon signaling, but also adaptive responses linked to the activity of CD\({}_{8}\) lymphocytes and Th\({}_{17}\)[19; 21]. There are at least fifteen chromosomal regions that contribute to psoriatic disorders, known as Psoriasis Susceptibility (PSORS), numbered from 1 to 15 [22].  
The _PSORS1_ maps to the major histocompatibility complex (MHC) on chromosome 6p21 and encompasses nine genes, alleles, or haplotypes of human leukocyte antigen (HLA) class I [22; 23]. _HLA-C_, Coiled-Coil Alpha-Helical Rod Protein 1 (_CHCR1_), and corneodesmosin (_CDSN_) genes are highly polymorphic in patients with PsV [24; 25]. The HLA-B^27, HLA-B^39, HLA-B^38, and HLA-B^08 are associated with a higher risk of PsA with HLA-B27 and HLA-B^39 earlier onset of PsV and PsA. The HLA phenotypes are also associated with different clinical manifestations of PsA, whereas HLA-B^08 is associated with asymmetric sacroiliitis, peripheral arthritis ankylosis, and increased joint damage, and HLA-B^27 is associated with symmetric sacroiliitis, dactylitis, and enthesis [26]. The _HLA-C_ encodes a receptor that participates in immune responses by presenting antigens to CD\({}_{8}\)+ T lymphocytes [27]. The HLA-Cw6 allele can present specific melanocyte autoanti (ADAMTS-like protein 5) to CD\({}_{8}\)+ T cells [24]. The HLA-C^06:02 is associated with an earlier onset of PsV and a later onset of PsA [28]. Corneodesmosin (CDSN) is involved in the production of the protein responsible for skin desquamation; however, its association with PsV is inconclusive [22; 27; 29; 30]. The _PSORS2_ locus contains the _Caspase Recruitment Domain Family Member 14_ (_CARD14_) gene, which is highly expressed in keratinocytes [31]. CARD14 is an adaptive protein that takes part in NF-kB signaling, leading to the production of proinflammatory cytokines [31]. Gain of function mutations in the _CARD14_ gene are associated not only with psoriasis but also with other inflammatory skin diseases: pityriasis rubra pilaris (PRP) and generalized pustular psoriasis (GPP) [19; 32; 33].  
Other _PSORS4_ region maps to chromosome 1q21 include the Epidermal Differentiation Cluster (EDC), which participates in definitive keratinocyte differentiation [22; 34]. Deletion of two genes from the _EDC_ region, _LCE3B_ and _LCE3C_, is associated with psoriasis and disruption of epidermal barrier function [34; 35; 36].  
Polymorphisms associated with PsV are reported in _IL-12B_, _IL-13_, _RUNX1_, _IL-23 receptor_ (_il23r_), TNF-regulated protein A20 (_TNFAIP3_), and tyrosine-protein phosphatase non-receptor type 22 (_TPPN22_) genes [37; 38; 39; 40]. Regarding other polymorphisms in _FTO_, _CALCR_, and _AC003006.7_ genes were found in patients with PsV that are also related to obesity [41]. Examples of gene polymorphisms associated with psoriasis and their clinical implications are presented in Table 1.