Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis

Abstract

Background: Hereditary hemochromatosis (HH) is an autosomal recessive disorder mainly associated with homozygosity for the C282Y and H63D mutations in the hemochromatosis (HFE) gene. The reports about the C282Y and H63D mutations and hepatocellular carninoma (HCC) were controversial. To clarify the relationship between C282Y and H63D mutations and HCC, a meta-analysis including nine studies (1102 HCC cases and 3766 controls, mainly came from European populations) was performed.

Methods: The association was measured using random-effect (RE) or fixed-effect (FE) odds ratios (ORs) combined with 95% confidence intervals (CIs) according to the studies' heterogeneity.

Results: Meta-analysis of nine studies showed that Y allele of C282Y was associated with HCC risk: RE OR reached 1.50 (95%CI: 1.05-2.14, p for heterogeneity = 0.02, I2 = 0.57). Subgroup analysis of seven studies also showed Y allele was associated with HCC risk in healthy populations: RE OR reached 1.61 (95%CI: 1.08-2.39, p for heterogeneity = 0.04, I2 = 0.55). We further did subgroup analysis in alcoholic liver cirrhosis (LC) patients of four studies (224 cases and 380 controls) and found that both the dominant model and Y allele of C282Y were associated with HCC risk (FE OR reached 4.06, 95%CI: 2.08-7.92 and 3.41, 95%CI: 1.81-6.41, respectively). There was no distinct heterogeneity among the studies (I2 = 0). Sensitivity analyses showed the results were robust in the subgroup analysis of alcoholic LC patients.

Conclusions: C282Y mutation was associated with HCC in European alcoholic LC patients.

Figure 1

Forest plot of the RE ORs and 95% CIs of the association between HCC and the C282Y mutation (Y vs. C) of nine studies. The combined estimate is indicated by the diamond. The solid vertical line represents the null result.

Figure 2

Forest plot of the RE ORs and 95% CIs of the studies on the association between HCC and the HFE C282Y mutation (Y vs. C) of seven studies (using healthy controls).

Figure 3

Forest plot of the FE ORs and 95% CIs of the studies on the association between HCC and the HFE C282Y mutation (YY+CY Vs. CC) of four studies (using alcoholic LC controls).

Figure 4

Sensitivity analysis of the association of C282Y (YY+CY vs. CC) and HCC among alcoholic LC patients of four studies, in which the meta-analysis estimates were computed omitting one study at a time. The results indicated the association was robust.