Although functional variants remain to be identified, we speculate that genetic variants at the IL4/IL13 locus contribute to the Th1 bias that is characteristic of psoriasis, that Th1-derived IFN-gamma supports expansion of IL-17+ T cells through APC-derived IL-23 and that negative regulation of inflammatory signaling through the NF-kappaB axis is impaired because of genetic variants of TNFAIP3 and TNIP1.
Recently the results of multiple, well powered, genetic case-control studies have begun to appear providing convincing statistical evidence for at least ten non-HLA related risk genes or loci (C5/TRAF1, CD40, CTLA4, KIF5A/PIP4K2C, MMEL1/TNFRSF14, PADI4, PRKCQ, PTPN22, STAT4, and TNFAIP3/OLIG3) for RA and six (IL12B, IL13, IL23R, STAT2/IL23A, TNFAIP3, and TNIP1) for psoriasis.
Association with psoriasis and psoriatic arthritis has been found in TNFAIP3 and TNFIP1, ubiquitin ligases in the NF-kappaB pathway, and IL13, a Th2 cytokine.
Recently, the results of multiple well-powered genome-wide association studies have identified several additional loci outside the major histocompatibility complex region associated with psoriasis risk, including three genes involved in interleukin (IL)-23 signaling (IL-23R, IL-23A, IL-12B), two genes that regulate nuclear factor-kappaB signaling (TNIP1, TNFAIP3), and two genes involved in the modulation of T-helper type 2 immune responses (IL-4, IL-13).
By demonstrating an association with therapeutic response, these results provide a clinically relevant functional correlate to the recently described genetic association between psoriasis and TNFAIP3.
We found that expression of TNFAIP3 mRNA in all patients negatively correlated with the psoriatic area and severity index (PASI) (r = -0.5126; P = 0.0004) as well as with the percentage of body surface area affected by psoriasis (r = -0.5013; P = 0.0005).
The aim of our study was to analyse the presence of three different psoriasis susceptibility genetic variations (HLA-Cw6; TNFAIP3rs610604 polymorphism; LCE3B/3C gene deletions) in a cohort of patients affected by moderate to severe psoriasis under ustekinumab treatment.
After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry.
Thus, the data suggested that HCP5, TNIP1 and TNFAIP3 may play a role in common pathogenic of psoriasis in Chinese and confer risk factors for psoriasis in various ethnic populations.
Genome-wide association studies in white and Chinese Han populations have found that the single-nucleotide polymorphism (SNP) rs610604, at the tumour necrosis factor (TNF)-α-induced protein 3 (TNFAIP3) locus, is associated with psoriasis, and is also associated with response to TNF blockade in psoriasis.
According to genome-wide association studies (GWAS), the TNIP1 gene, which encodes the TNF-α-induced protein 3-interacting protein 1 (TNIP1), is strongly linked to the susceptibility of psoriasis.