Although the precise mechanism of human psoriasis remains somewhat enigmatic. It is increasingly recognized that strong genetic predisposition act as an intrinsic factor for psoriasis pathogenesis, and SNPs in the human genome may be one of the keys to unlock insights into the genetic basis for the occurrence, development and relapse of psoriasis32,33. As intrinsic factors, polymorphisms in TNFAIP3 and TNIP1 gene has garnered considerable attention over the past decade years by different research teams all over the world.
Our results indicated that there is a statistically higher frequency of the rs610604 G in psoriasis patients. Most individual studies were in accordance with the result analysis by synthesis. The results of the meta-analysis remained unchanged when we conducted the leave-one-out sensitivity analysis. For rs17728338, the pooled outcome illustrated that the A allele of rs17728338 has a significantly increased risk for psoriasis. To further explore the underlying mechanisms of the interaction of TNFAIP3 and TNIP1, the HaploReg 4.1 online database was used to predict the functions of the two loci in silico. According to HaploReg, enhancer histone marks for rs610604 were found in 5 different human tissues, while enhancer histone marks for rs17728338 were found in 9 different human tissues. Both rs610604 and rs17728338 were in linkage disequilibrium with numerous other loci using a threshold of r2 ≥ 0.8. Regulatory motifs changed were found in both rs610604 and rs17728338. These in silico information may help to have a better understanding of the functions of the two loci, and functional experiments are strongly needed to validate these hypotheses in the future.
A20 was first characterized as a cytokine‑inducible factor by a seminal study of Dixit, V. M. et al. in 199034. After that, in the year of 2004, Dixit and co-workers discovered that A20 was involved in TNF-induced NF-кB activation by playing the role of dual ubiquitin-editing enzyme35,36. Dysregulation of A20 expression was found to be associated with inflammatory and autoimmune disease such as psoriasis as well as the pathogenesis of cancer over the past few years. Jiang et al.’s study37 suggested that TNFAIP3 mRNA expression level significantly correlated with the severity and pathology of psoriasis. Other studies on systemic lupus erythematosus (SLE) and type 2 diabetes reported that some of the single nucleotide polymorphisms (SNPs) could influence the expression level of the TNFAIP338,39. As for cancer involvement, A20 mRNA was found to be upregulated in the poorly differentiated head and neck squamous cell carcinomas (SCCs) of the skin while no A20 mRNA is observed in normal tissues samples40. The molecular mechanism of A20 functions underlying these biological processes is generally characterized as the inhibitory effect of NF-κB activation by editing the ubiquitylation status of its numerous proximal signaling proteins such as receptor-interacting protein serine/threonine kinase 1 (RIPK1), TNF Receptor Associated Factor 6 (TRAF6), Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT1), etc41,42. Apart from NF-κB signalling pathway, A20 has also been reported to be involved in the regulation of other signalling circuits including Wnt pathway, interferon regulatory factor (IRF) pathway, etc43,44. There were also studies focusing on blocking autophagy and anti-apoptotic activities by deubiquitination45. However, the exact mechanisms by which it does this remains unclear. More researches are needed to explore the mechanisms underlying them.
One of the most critical A20 binding protein is TNFAIP3 Interacting Protein 1 (TNIP1), which has another alias of ABIN-1. It has been reported that TNFAIP3 and TNIP1 physically interact with each other to inhibit cell death and NF-κB signalling pathway46,47. Similar with TNFAIP3, more than 3 genome-wide association studies (GWAS) indicated that TNIP1 had been implicated in numerous inflammatory disease, including psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), systemic sclerosis (SSC), rheumatoid arthritis (RA)19,27,48-50. It is probably that A20 collaborate with TNIP1 to be involved in the pathophysiology of these diseases.
To date, this is the first comprehensive study on the correlation between TNFAIP3 and TNIP1 polymorphisms and psoriasis vulnerability. However, several drawbacks should not be overlooked. First, as far as a limited number of studies are concerned, although we have collected all the currently related data, false negatives of our study may exist. Second, the genetic factor for psoriasis is composed of multiple genes and loci. However, we only concentrated on rs610604 in TNIP1 and rs17328338 in TNFAIP3 in this work. Third, only the allele model was used to analyze the data. Other genetic models are strongly recommended to be used as long as there are enough future relevant researches. Fourth, the HWE of some included studies were missing, which may lead to Information bias. Finally, only studies published in English were finally included in the present study, which may lead to selection bias.