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.
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.
Moreover, a significant negative correlation was found between TNFAIP3 mRNA in psoriatic tissue and psoriasis area severity index values (rs = -0.382, P-value = 0.037).
Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022).
The association between tumor necrosis factor-alpha induced protein 3 interacting protein 1 (TNIP1) gene and psoriasis was confirmed in people with multiple ethnicities.
Thus, our results suggest that TNFAIP3 (rs610604) and TNIP1 (rs17728338) polymorphisms confer increased risk of psoriasis and may play a vital role in its pathogenesis in our ethnic South Indian Tamils.
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.
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).
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.
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.
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.
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.
In addition, there are numerous other genetic susceptibility loci (LCE3, CARD14, NOS2, NFKBIA, PSMA6, ERAP1, TRAF3IP2, IL12RB2, IL23R, IL12B, TNIP1, TNFAIP3, TYK2) and geoepidemiologic factors that contribute to the wide variability seen in psoriasis.
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.
When we compared type I psoriasis with type II psoriasis (N = 36), we found a significant association between age at onset and the genes PSORS6, TNF-α, FCGR2A, TNFR1, CD226, HLA-C, TNFAIP3, and CCHCR1.
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.