Chronic hepatitis C virus infection is considered a major risk factor for HCC development [13]. As an RNA virus, HCV does not integrate into the host genome, so pathogenesis of HCV-related HCC is proposed to involve generation of oxidative stress and increased expression of inflammatory cytokines associated with chronic hepatitis [14], in addition to the direct effect of HCV viral products [15].
Interleukin-4 (IL-4), a pleiotropic anti-inflammatory cytokine, is involved in humoral and cell-mediated immunity [16]. It suppresses a number of pro-inflammatory cytokines and expands anti-inflammatory effect [17]; thus, it is suggested that any alterations that influence IL-4 expression or function may disturb immune responses increasing the liability to infections.
In addition, IL-4, together with other Th2 cytokines, induces M2 macrophage polarization. Traditionally, macrophages are classified into classically activated M1 phenotype and the alternatively activated M2 macrophages according to their responses to different microenvironmental stimuli [18].
M2-polarized macrophages are main components of tumor-infiltrating stromal cells. They are key factors participating in tumor progression. M2-polarized macrophages were also related to promote tumor growth, invasion, and metastasis by secreting certain chemokines growth factors, cytokines, and matrix metalloproteases [19].
IL-4 gene is located on chromosome 5q31 [17]. In the current study, we aimed to study the contribution of promoter polymorphism of IL-4 -589C/T (rs2243250) to the susceptibility of HCV-related HCC. It had been stated the T allele of IL-4 (-589C/T) polymorphism is associated with an increased IL-4expression [20].
Our study showed that TT genotype was more prevalent in HCC group (24%) compared to control group (3.3%) and cirrhotic patient group (5%). TT homozygous genotype had 10 times more risk of hepatocellular carcinoma versus healthy control group and 6.33 times more risk versus cirrhotic patients group (p value = 0.018 and 0.016, respectively). The T allele frequency was increased in HCC group (44%) versus (26.7% and 28.8%, OR (95% CI) = 2.16 and 1.95) in control and cirrhotic patients group, respectively.
This was consistent with the study led by Khalil et al. among HCV-infected Egyptian patients, they reported that IL-4-589 TT genotype was significantly increased in HCV-infected patients (p = 0.001) with strong reduction in the control group (3.3%), the patients samples revealed only CT (82%) and TT (18%) genotypes [21].
Also, there was a study conducted by Yousif et al. among HBV-infected patients in Sudan. They noted that CT and TT genotypes were 73.2% and 19.6%, respectively among infected patients [22].
In addition, the meta-analysis study directed by Zheng et al. who reported significant association between the IL4-589T polymorphism and increased risk of liver diseases in Caucasian populations; however, this was not detected in Asian populations [23].
It is worth noting that in our study, the significant association of IL4-589C/T polymorphism among HCC patient group was related to TT genotype which was contrary to the CC genotype detected in chronic HBV-infected Chinese male patients in the study conducted by Lu et al. in 2014 [24].
It is proposed that there are differences in the IL-4 genetic background among different ethnic groups. As on studying genotype distribution and allele frequency in control group of our study, the IL4−589 C allele frequencies were (73.3%), which were similar to healthy Egyptian (61.7%) and healthy Caucasians results (86.3%) in the studies conducted by Khalil et al. in 2017 [21] and Zheng et al. in 2013 [23] respectively but higher than frequencies among healthy Chinese (17.4%) in the study conducted by Lu et al. [24], while the T allele frequencies accounted for (26.7%), which was similar to healthy Egyptian (38.3%) [21] and healthy Caucasians frequency results (13.7%) [23] but was lower than that of healthy Chinese (82.6%) [24]. Thus, the T allele may be the variant responsible for various diseases in Egyptian population, while the opposite is true for Chinese population. This suggests that distinct allele frequencies in the same polymorphism site may play different roles in the same disease. A larger-scale multicenter study is recommended to confirm this suggestion.
On the other hand, we studied size and number of foci lesions in HCC group in relation to recessive genetic model of -589C/T SNP (CC + CT vs TT), we did not find statistical significance between 2 groups.