# Soriasis and Seasonality: Exploring the Genetic and Epigenetic Interactions
## 4 Environmental Factors Affecting Psoriasis
### Circadian Rhythm  
[PERSON] et al. [156] reported a higher risk of incidence of psoriasis and psoriatic comorbidities in rotating night shift healthcare workers. This phenomenon can be explained by lower exposure to sunlight, decreased vitamin D levels, reduced production of melatonin, or a tendency to behavioral disruptions, but also by the circadian rhythm's disturbance. A similar study by [PERSON] et al. [157] had comparable results in urticatic incidence. The circadian rhythm is regulated by the so-called master clock located in the suprachainstatic nucleus (SCN) and affects molecular clocks in peripheral tissues [158; 159; 160]. The molecular mechanism of the circadian rhythms is based on the transcription-translation positive and negative feedback loops of circadian clock genes and their proteins [161]. The positive arm of the circ clock gene network consists of the transcription factor Brain and Muscle ANT-like 1 (_BMAL1_) and Circadian Locomotor output Circle (_CLOCK_), which form heterodimers binding the enhancer box to active transcription of Period (_Per_) 1, 2, and 3 and Cryptochrome (_CRY_) 1 and 2. PER and CRY drive the negative arm by inhibiting the expression of _BMAL1-CLOCK_ genes, leading to the impediment of their transcription. Decreased levels of PER and CRY factors conduct the BMAL1-CLOCK activation, completing the circle within 24 h. Other clock-controlled genes associated with circadian rhythms within the SCN are RAR-related orphan receptors (RORs) and REV-ERBS-response elements (RORE), which form a secondary feedback loop influencing the oscillatory expression of the _BMAL1_ gene [160]. The light causes the retina's neuronal and hormonal signaling, activating the SCN [158]. Neurotransmitters involved in this process, vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP), along with the astrocytes, stabilize the circadian clocks within the SNC [158; 159; 160]. Peripheral tissues' clocks, for example, skin, are also influenced by environmental factors, such as temperature, activity, and food intake [162; 163]. The increased risk of psoriasis appears to be linked to disturbances in circadian rhythms [164; 165; 166; 167; 168; 160]. The direct link between Th\({}_{17}\) cell differentiation and the circadian clock was first described by [PERSON] et al. in 2013 [169]. Expression of _NFIL3_ suppresses Th\({}_{17}\) cell development by repressing orphan receptor ROR\(\gamma\)t transcription. _CLOCK_, _PER2_, and _BMAL1_ genes also play a significant part in the transcription of IL-23R in \(\gamma/\beta^{+}\) T cells. Mutations in these regions are associated with the induction of psoriatic symptoms [165]. BMAL1, CRY, ROR\(\alpha\), and REV-ERB\(\alpha\) proteins are positive regulators of the anti-inflammatory reactions [165]. Downregulation of these proteins enhances inflammation. CLOCK protein, however, can promote inflammation via the NF-\(\kappa\)B pathway. Circadian genes such as _CRY2_, _PER3_, _NRID1_, and _RORC_ are downregulated in psoriatic lesions and the adjacent normal skin compared to the skin from non-pyoriatic individuals [170]. The mRNA expressions for IL-17A, IL-22, and IL-23 are strongly associated with circadian genes and elevate at night, decrease at dawn, and then increase during the day [165]. The disruption of the _REV-ERB\(\alpha\)_ gene, which suppresses ROR\(\gamma\)t-driven Th\({}_{17}\) cell differentiation, also seems to be involved in developing psoriasis and psoriatic arthritis symptoms [171]. A study conducted by [PERSON] et al. [172] on the mice [PERSON]/C went through selective paradoxical sleep deprivation, which led to immunological disturbances in mice. The authors observed increased levels of proinflammatory cytokines IL-1, IL-6, and IL-12 and decreased levels of the anti-inflammatory cytokine IL-10 in tested mice. Another study investigated the potential reciprocal relationship between the circadian clock, feeding time, and skin inflammation exacerbation [173].