HH is a common genetic disease in European populations that causes an inappropriately high absorption of iron, leading to the progressive accumulation of iron in the liver. The two missense mutations C282Y of the HFE gene explain most of the cases of HH, a condition characterized by hepatic iron overload. Liver iron accumulation leads to reactive oxygen species formation in the liver, thus causing oxidative stress. It has been shown that the wild-type HFE protein forms a stable complex with the transferrin (TF) receptor (TFR), thereby reducing its affinity for TF [32
], whereas the HFE 282Tyr mutation almost completely prevents the formation of a complex between the mutant HFE protein and the TFR, allowing a high-affinity TF binding to the TFR. This binding results in an increased cellular uptake of iron. A second missense mutation in the HFE gene, H63D, is found in about 4% of patients with HH, but its role in iron overload is still debated [6
It has been reported that HCC occurred more in HH patients than in normal populations in some cohort studies [4
]. However, there are also opposite reports that HH had low penetrance and did not increase the risk of HCC [20
From the late 1990s, many researchers have explored the relationship between these two mutations and HCC susceptibility by using case-control or cohort studies [7
]. In 2007, Christina Ellervik and her colleagues [37
] performed a meta-analysis to examine associations between C282Y and H63D mutations with HCC. The meta-analysis included nine studies and reported that C282Y homozygotes YY versus CC obtained an odds ratio of 11 to HCC occurrence. However, the sample sizes of many studies included in that meta-analysis were too small, leading to low statistical power. From then on, several articles about HFE mutations and HCC have been published. We selected nine eligible studies including 1102 cases and 3766 controls to conduct an updated meta-analysis.
Because HH is more frequent in northern European populations, the studies on HFE gene mutations and HCC are mainly come from European ethnicities. In this meta-analysis, eight studies were come from Europe and one from Africa. So, the analysis results may be mainly applicable to European populations and it warrants to be studied in other ethnicities. In this meta-analysis, the frequency of C282Y YY homozygotes was 0.42% (16/3766), and the frequency of CY heterozygotes was 9.32% (351/3766) in all control subjects. The genotype distribution was consistent with the dbSNP data. H63D genotype distribution was 2.66% (60/2258) and 23.78% (537/2258) for DD homozygotes and HD heterozygotes in controls, respectively.
As to C282Y, the ORs of allele contrast (Y vs. C) in the six studies [8
] were larger than 1.0. Among the six studies, four studies [8
] reported a significant association between HCC and the C282Y polymorphism (ORs > 1.0, 95%CIs did not include 1.0). Because the frequency of the homozygous mutation of C282Y is very low, and a large proportion of C282Y homozygotes had been diagnosed with HH and received treatment, such as venesection before developing LC or HCC, the conclusion that YY homozygotes increased HCC risk may have little clinical value. Thus, we only explored the dominant model and allele contrast in this meta-analysis. This meta-analysis proved that C282Y mutation was associated with HCC in European populations, especially in alcoholic LC patients but not in viral LC patients. This result is consistent with the results of three previous studies [8
], and it may implicate that the hepatocarcinogenesis of alcoholic LC and viral LC is different and warrants further study. Some studies explored the role of gender in the influence of the relationship between HFE gene and HCC [10
] and found that C282Y homozygotes YY mutation increased the risk of HCC in male patients. One English study [10
] reported that male C282Y homozygotes were more likely to be diagnosed with HCC (OR = 14, 95%CI: 5-37), and the penetrance of the C282Y homozygous genotype, with respect to HCC, was between 1.31% and 2.1% for males and zero for females. Another study [36
] reported that C282Y homozygote males had a relative risk (RR) of about 23 for HCC occurrence, and the penetrance, with respect to HCC, was 5.56%. As there were few studies that provided concrete gender subgroup genotype values, we could not make a pooled analysis.
From the pooled genotype data, we could assess the statistical power under various subgroup analyses using PS software [27
]. We noted that the power was satisfactory except when comparisons were performed between HCC cases and viral LC patients (power = 0.09). This indicated that the null association of C282Y and HCC when compared in HCC cases and viral LC cases should be taken with caution and that it warranted further study in a larger scale. FPRP is a valuable criterion to assess whether or not a positive discovery came about by chance. We used FPRP to assess the positive association attained by this meta-analysis. The association between C282Y (Y vs. C) and HCC attained by subgroup analysis of four studies using alcoholic LC patients as controls was proved to be reliable (FPRP = 0.03).
Population-attributable risk (PAR) is a valuable parameter to assess the influence of risk factors on disease occurrence. The PAR of the variant allele Y of C282Y among alcoholic LC patients was 5.12% (95%CI: 2.57%-7.67%). This result suggested that the role of C282Y polymorphism on HCC occurrence was modest.