Table 2.
Key pathways to which psoriasis genetic susceptibility factors localize.
| Biological Pathway | Representative Susceptibility Genes | Possible Role/s in Psoriasis | Target Drugs |
|---|---|---|---|
| HLA mediated antigen presentation | HLA-C*06:02, HLA-A, HLA-B and HLA-DQ [176,177]. | Facilitates presentation of autoantigens [171,172]. | No targeted drug currently. HLA-C*06:02+ individuals respond better to the anti-IL-12/IL-23 biologic ustekinumab [178]. |
| NF-kB signalling | FASLG, IKBKE, NFKBIA, REL, SLC44A2, TNFAIP3, TNIP1, TRAF3IP2 [179] and CARD14 [180]. | Elevates innate immune responses, activates T helper cells and reduces keratinocyte death [181]. | Fumarate and apremilast inhibit NF-kB activation [182]. |
| Th17 cell activation | IL23R, IL23A, IL12B [183]. | Compels keratinocyte proliferation and promote psoriatic inflammation [132]. | Biologics targeting IL-23 (tildrakizumab, guselkumab, risankizumab, and ustekinumab), novel RORγ inhibitors and JAK inhibitors [184,185]. |
| Skin structure proteins | The LCE3 gene cluster, KLF4, COL6A5 and COL8A1 [173,175,186]. | LCE3 and KLF4 genes facilitate cornified envelope production, and their variants contribute to barrier dysfunction [187]. COL6A5 regulates cell adhesion and proliferation and COL8A1 mediates vascularisation [186]. | Topical calcitriol may operate by upregulating LCE genes [188]. |
| Keratinocyte proliferation and differentiation | Keratins 6, 10, 14, 16 and 17 [26,189]. PDCD5, PTEN and CHUK [179,190]. | Keratin 10, 14, 16 and 17 variants, reduced keratin 1 and 10 levels and elevated keratin 6, 16 and 17 levels associate with keratinocyte hyperproliferation and aberrant differentiation [23,26,189]. PDCD5 is hypermethylated, reducing its expression and capacity to facilitate apoptosis [190]. IKKa (the protein CHUK encodes) and PTEN typically regulate differentiation and proliferation, respectively [191,192]. |
Topical calcineurin inhibitors and vitamin D receptor agonists, such as calcitriol and retinoids, prevent atypical keratinocyte proliferation and differentiation [193]. |
| Type 1 IFN signalling | DDX58, IFIH1 and RNF114 variants [180,194]. | Sensitises keratinocytes to IL-22, induces the maturation of cDCs and facilitates the differentiation of naïve CD4+ cells [6,90]. | UVB phototherapy downregulates IFN signalling pathways [195]. Novel IL-36 inhibitors may modulate IFN responses [196]. |
Abbreviations—CARD14: caspase recruitment domain family member 14; CCL: chemokine ligand; CHUK: component of inhibitor of nuclear factor kappa B kinase complex; DDX58: DExD/H-Box helicase 58; FASLG: fas ligand gamma; HLA: human leukocyte antigen; IFIH1: interferon induced with helicase C domain 1; IKK: IκB kinase; IKBKE: inhibitor of NF-kB kinase subunit epsilon; IL23R: interleukin-23 receptor; JAK: Janus kinase; KLF4: Krüppel-like factor 4; LCE: late cornified envelope; NF-kB: nuclear factor-κB; NFKBIA: NF-kB inhibitor alpha; PTEN: phosphatase and tensin homolog; PDCD5: programmed cell death 5; RNF114: ring finger protein 114; RORγ: retinoic acid receptor-related orphan receptor gamma; SLC44A2: solute carrier family 44 member 2; TNFAIP3: TNF alpha induced protein 3; TNIP1: TNFAIP3 interacting protein 1; TRAF3IP2: TRAF3 interacting protein 2; UVB: ultraviolet-B.