TNFAIP3 gene has been recognized as a major susceptibility gene for multiple auto-immune diseases . Recently, GWAS revealed that there is a strong association of multiple SNPs in the TNFAIP3 gene, located on human chromosome 6p23, and psoriasis . Subsequent studies confirmed its implication in other immune-mediated disorders, such as rheumatoid arthritis (RA), juvenile idiopathic arthritis, SLE , inflammatory bowel disease (IBD) , and ITP. The list of common variants in TNFAIP3 gene keeps expanding, with reported associations with several auto-immune diseases including ITP; however, little is known about the role of TNFAIP3 in the pathogenesis of ITP . The current case-control study aimed to study the distribution of TNFAIP3 (rs5029939: C>G) polymorphism and the possible association of the studied polymorphism with the susceptibility to chronic PIT and the response to treatment in a sample of Egyptian pediatric chronic PIT patients. TNFAIP3 genotyping was tested by PCR-RFLP technique in 40 pediatric chronic PIT patients. Fifty age- and gender-matched healthy controls were subjected to the same analysis.
TNFAIP3 (rs5029939 C>G) genotyping revealed a statistically non-significant different distribution among chronic PIT cases and controls [CC, 77.5% vs. 82.5%, and CG, 22% vs. 18%, respectively; OR (95% CI), 1.323 (0.470–0.723); p, 0.596]. The MAF of rs5029939-G was comparable between the 2 groups (0.11 vs. 0.09) [OR (95% CI), 1.282 (0.484–3.397); p, 0.617] (Table 3). Thus, this study demonstrated no statistically significant different TNFAIP3 (rs5029939 C>G) genotype distribution or allele frequency between chronic PIT patients and controls with no liability of patients carrying TNFAIP3 (rs5029939 C>G) polymorphism to develop chronic course of the disease. Comparison between chronic PIT patients carrying the mutant heterozygous genotype (CG) achieving complete response and those with no response revealed non-statistically significant difference between both groups [OR (95% CI), 1.667 (0.165–16.810); p > 0.05]. Similarly, the MAF of rs5029939-G was comparable between both groups [OR (95% CI), 1.571 (0.175–14.111); p > 0.05] (Table 5). Thus, this study showed no liability of patients carrying TNFAIP3 (rs5029939 C>G) polymorphism to achieve complete response to treatment. So we concluded that the variant genotype (CG) and the minor allele (rs5029939-G) are not risk factors for the susceptibility to chronic PIT and are not associated with response to treatment in the studied sample of Egyptian pediatric patients with chronic PIT.
Our results agreed with those of Li et al.  who investigated the frequency of four TNFAIP3 SNPs (rs5029939, rs2230926, rs6920220, and rs10499194) in the Chinese population. Compared to controls, only (rs10499194) SNP expression was significantly higher in ITP patients, while there was no statistically significant difference in genotype and allele frequencies regarding other SNPs including (rs5029939) between ITP subjects and controls. Moreover, no significant association of the studied SNPs with the severity or refractoriness of ITP was observed.
However, our results were discordant with those reported by Zhou et al.  who investigated TNFAIP3 (rs2230926 T>G) and (rs5029939 C>G) SNPs in the Chinese patients. They demonstrated that both (rs2230926 T>G) and (rs5029939 C>G) variants showed a statistically significant different genotype distribution between Chinese chronic PIT patients and controls [(TG, 23.3% vs. 9.8%) OR (95% CI), 2.79 (1.51–5.18)], p < 0.05, and [(CG, 30.1% vs. 7.2%) OR (95% CI), 5.57 (2.83–10.97)], p < 0.05. Similarly, the minor alleles (rs2230926)-G and (rs5029939)-G showed a statistically significantly higher frequency in chronic PIT patients compared to controls (11.6% vs. 4.9%) [OR (95% CI), 2.56 (1.41–4.64)], p < 0.05, and (15.1% vs.3.6%) [OR (95% CI), 4.76 (2.47–9.17)], p < 0.05, respectively. So they concluded that there is a statistically significant difference in TNFAIP3 (rs5029939 C>G) genotype distribution and allele frequency between both groups and that the variant genotypes of rs2230926 (TG) and rs5029939 (CG) and the mutant alleles (rs2230926)-G and (rs5029939)-G are risk factors associated with the susceptibility to chronic PIT in Chinese children. The difference between their results and ours might be explained by the fact that the TNFAIP3 (rs5029939 C>G) variant genotype (CG) are variably expressed among different ethnic populations being more expressed in Chinese than Egyptian population, also environmental variation and epigenetic factors are kept in consideration. Besides, the potential for ancestry differences and admixture to affect the results of their genetic analyses
Zhou et al.  had concluded that TNFAIP3 (rs2230926 T>G) and (rs5029939 C>G) SNPs might be associated with the susceptibility of chronic PIT in Chinese population, suggesting that TNFAIP3 gene might be added to the list of genes associated with chronic PIT. However, by this time, no previous researches were conducted to explore the effect of (rs5029939) variant located in Intron 2 on TNFAIP3 function in ITP patients, so they recommended further studies to explore the mechanisms how these two variants modulated the susceptibility of the disease. Moreover, Dieudé et al.  showed that (rs5029939) was in strong LD with (rs2230926) in European Caucasian population. However, unlike the European Caucasian population, Zhou et al.  did not find a tight LD between both variants in Chinese population. So further studies to explore the role of (rs5029939) variant in the pathogenesis of PIT as well as the LD between (rs5029939) and (rs2230926) were recommended.
As regards studying TNFAIP3 (rs5029939 C>G) variant in other auto-immune diseases, our results agreed with those of Yang et al.  who investigated the frequency of TNFAIP3 (rs5029939 C>G) SNP in the Chinese population with myasthenia gravis (MG). Compared to controls, TNFAIP3 (rs5029939 C>G) SNP expression was not significantly higher in patients’ group. The distribution of the variant genotypes in the MG subjects and controls [CG, 8% vs. 8.1, and GG, 0.5% vs. 0%, respectively, p 0.880]. The minor allele (rs5029939-G) was comparable between MG patients and controls (4.5% vs. 4%), p 0.750. So it was concluded that the variant genotypes (CG/GG) and the minor allele (rs5029939-G) were not risk factors for the susceptibility to MG disease. A meta-analysis was done by Lee and Song  who considered 8 studies of ethnically different groups (4 Asian [16, 22, 25, 26], 3 European [18, 27, 28], and one African American ), to investigate whether the TNFAIP3 polymorphisms including (rs5029939 C>G) SNP contribute to SLE susceptibility in different populations. They found out that the allelic frequencies of genes often differ considerably in different ethnic groups, and thus ethnically specific association studies are required to determine genetic associations in different populations. They confirmed the association of TNFAIP3 (rs5029939 C>G) SNP with SLE in Europeans and Asians. These findings suggest that the role of TNFAIP3 polymorphism in immune-mediated diseases is controversial and might be organ-specific.