The development of HCC is a complicated and multi-factorial process, in which both environmental and genetic factors play a role in carcinogenesis. The association between SNPs and HCC has been reported by numerous studies. These genetic traits may alter the natural history of cirrhosis and explain to some extent the observed differences in the risk of HCC development [16].
Interestingly, SNPs in the VDR gene are implicated in carcinogenesis in different organs such as the breast, prostate, skin, colon and rectum, and kidneys [17].
Here, we investigated the relationship between ApaI and TaqI VDR gene polymorphisms and HCC in patients with HCV-related liver cirrhosis.
We demonstrated that cirrhotic patients with HCC on top had a significantly higher frequency of VDR ApaI CC genotype compared to those patients who do not have HCC. Our results agree with previous studies [5, 15, 18, 19]. Some studies are matching us; they did not find a significant association between HCC and TaqI polymorphism [5, 15].
We investigated the implication of VDR ApaI and TaqI polymorphisms on the liver disease severity in both liver cirrhosis and HCC patients. The carriage of the ApaI CC genotype had significantly more severe liver disease (Child C and higher MELD score) compared to ApaI CA/AA genotypes, while the carriage of TaqI genotypes was not related to disease severity. These results came in agreement with Hung et al. [5] and Mohammed et al. [15].
On the contrary, Triantos et al. [20] reported that the carriage of VDR ApaI AA and TaqI AA genotypes was associated with more severe liver disease compared to ApaI CC/CA and TaqI GG/GA genotypes, respectively. This conflict could be simply explained by the difference in the inclusion criteria as Triantos et al. [20] investigated patients with chronic liver disease whatever the cause (viral, autoimmune, cryptogenic, etc.) and not complicated by HCC on top, while in our study, we selected only the HCV-related cirrhotic patients.
On addressing the risk factors for the development of HCC among HCV-related liver cirrhosis patients in this study, univariate binary logistic regression analysis was performed on age, sex, smoking, diabetes mellitus, Child and MELD scores, platelet count, and VDR ApaI and TaqI genotypes. Only platelet count and the carriage of the ApaI CC genotype were the factors significantly associated with HCC development; this was confirmed by multivariate binary logistic regression analysis.
The present study reported that the carriage of the ApaI CC genotype was an independent risk factor, proposing that the ApaI CC polymorphism may be a good molecular marker to predict the risk of HCC in patients with HCV-related liver cirrhosis. This agrees with Asal et al. [18] and El-Edel et al. [19]. Additionally, the ApaI CC genotype was reported to be associated with HCC development in non-cirrhotic patients with chronic HCV [5, 15].
Related studies of several polymorphisms in the VDR gene have been done to investigate their implication on the risk of HCC, although with different results. Falleti and his colleagues [21] demonstrated that the carriage of the BsmI GG and TaqI TT genotypes were significantly associated with HCC development in post-liver transplantation patients. However, this study was performed more particularly on patients with alcoholic cirrhosis, not other etiology of liver cirrhosis, where the carriage of the BAT [ATC] and [GTT] haplotypes was independently associated with an increased risk of HCC. This discrepancy could be explained by the low number of patients in the subgroup analysis of virus cirrhotic patients.
Peng et al. [10] reported that the carriage of the FokI TT/CT genotypes was associated with increased HBV-related HCC risk as compared to the FokI CC genotype. Some investigators in previous researches [15, 22,23,24] have reported that the carriage of the FokI TT genotype had a significantly higher risk for HCC after adjustment of other associated risk factors in those chronically infected with viral hepatitis. In addition, it was found that the FokI TT genotype was associated with advanced tumor stage and lymph node involvement.
On the contrary, Huang et al. [25] reported that VDR polymorphisms could influence the distinct clinical phenotypes in HBV carriers, but are not associated with HCC proposing a limited role of the VDR gene polymorphisms in carcinogenesis. However, a biochemical evidence obviously reported the inhibitory effect of vitamin D and its analogs on HCC cells [26]. Moreover, it had been described that the antiproliferative effect of vitamin D against malignant cells depends on the intracellular VDR level [27, 28].