Association between IL-18 polymorphisms, serum levels, and HBV-related hepatocellular carcinoma in a Chinese population: a retrospective case–control study
HBV infection remains a public health problem worldwide, being endemic in some regions
of the world, especially in developing countries 36]. HBV can lead to severe liver diseases such as chronic hepatitis, cirrhosis, and
HCC 37]. HBV-infected individuals are at a higher risk of developing HCC 38], and age, sex, alcohol consumption, and smoking status are well known risk factors
contributing to HCC incidence 39], 40]. However, these factors do not fully account for the underlying mechanisms in HCC
development, indicating that the immune status of individuals may play pivotal roles
in disease progression. Through its involvement in the pro-inflammatory cytokine network,
IL–18 is an important mediator of innate and adaptive immunity. Polymorphisms of this gene
have been reported to influence the expression of IL-18 and may further lead to an
alteration in an individual’s immune status, thus increasing carriers’ susceptibility
to HCC development. However, this hypothesis is only partially confirmed herein.
In the present study, the IL–18 ?137G/C polymorphism was observed to be significantly associated with HCC. The GC
genotype and C allele of this SNP were associated with a significantly decreased risk
of HCC compared with the GG genotype and G allele. Similarly, the A
?607
C
?137
haplotype was significantly associated with a lower risk of HCC. Our findings were
consistent with those of previous studies on IL–18 polymorphisms and HCC risk 32]–34], all of which observed a significant relationship between the ?137G/C polymorphism
and HCC risk, with a high G allele frequency being associated with an increased risk
of HCC and, conversely, a low C allele frequency being associated with a decreased
risk of HCC. However, they also found a significantly increased frequency of the ?607
C/A AA genotype in HCC patients (AC genotype in Kim et al.’s study 32] ), while we observed a null association between them.
These controversial results may due to the underlying genetic differences between
various populations. In a study investigating the relationship between HBV infection
and IL–18 promoter polymorphisms among three minority populations in Yunnan province, China,
the genotype and allele frequencies of all three SNPs in the IL–18 promoter (?607 C/A, ?137G/C, and ?656G/T) were found to have distinct distributions
41]. Further, the authors observed a significant difference in HBV infection among the
three minority populations, concluding that the difference in genetic background among
the various ethnicities may be an important factor responsible for HBV infection susceptibility
41]. The present study was carried out in the Guangxi district, which is also ethnically
diverse, and our study population contains both Han and Zhuang ethnicity—this may
be the major contributing factor to the inconsistency result found in ?607C/A polymorphism.
With regard to the serum IL-18 levels, they were found significantly lower in HCC
patients compared to healthy subjects in the present study, such result is controversial
to many studies. For instance, researches by Tangkijvanich et al. 42] and Mohran et al. 43] showed that IL-18 levels in HCC patients were significant higher than those in healthy
controls, the latter study further concluded that serum IL-18 level was a suitable
diagnostic marker in HCV-related HCC patients. However, though Wen et al. 44] also observed significant differences in the transcription and expression levels
of IL-18 among different HBV infector groups; interestingly, the highest was found
in the fulminant hepatitis group and the lowest in the asymptomatic carrier group,
and no significant differences between the chronic hepatitis and normal control groups
were observed. These results indicate that serum IL-18 levels may be distinct at different
disease stages. On the other hand, as all patients in our study were HBV-related HCC,
with hepatitis B surface antigen, HBV core antibody, hepatitis Be antigen, or hepatitis
Be antibody seropositive for at least 6Â months, the majority of them have gone through
antiviral treatment; but, according to He et al. 45], antiviral treatment (pegylated interferon alpha) can induce a marked decline in
IL-18 and remission of hepatic inflammatory in HCV infectors. These may be the underlying
factors for the inconsistent results observed herein.
Furthermore, no association between the two IL–18 SNPs and IL-18 serum levels were observed in our study, which is inconsistent with
previous reports. In the study conducted by Giedraitis et al. 23], three alleles from the IL–18 promoter region (at positions ?656, ?607, and ?137) were cloned and transfected into
a HeLa cell line, leading to a tenfold higher IL–18 gene fragment activity compared to the negative control. This indicated that all
three polymorphisms had a clear promoting activity and were able to influence the
expression of IL-18. However, Giedraitis et al. 23] only conducted studies on gene expression level, which were not fully representative
of the transcription levels and, thus, of secretion levels. Therefore, our study is
the first to show that ?607 and ?137 polymorphisms are not associated with the expression
of IL-18 in serum. Nevertheless, since serum IL-18 levels may be affected by various
factors, some of these may mask the gene polymorphism effects.
In summary, the ?137G/C polymorphism of the IL–18 gene was observed to be significantly correlated with HCC risk. The A
?607
C
?137
haplotype of the ?607C/A and ?137G/C SNPs was also associated with a decreased risk
of HCC. These results indicate that the ?137G/C SNP in IL–18 may be a protective factor against HCC. Further, lower serum IL-18 levels were found
in HCC patients, however, the IL–18 ?607C/A and ?137G/C polymorphisms were not associated with IL-18 serum concentration.
Considering the limited study population included herein, additional studies with
larger samples and detailed clinical data are warranted in various ethnic populations.