Jin et al. Journal of Experimental & Clinical Cancer Research 2010, 29:18 http://www.jeccr.com/content/29/1/18 R E S E A R C H Open Access Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis Fei Jin, Li-Shuai Qu, Xi-Zhong Shen* 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. Background Hepatocellular carninoma (HCC) is the fifth most com- mon cancer in the world and the third most common cause of cancer mortality [1]. Hereditary hemochroma- tosis (HH) is an autosomal recessive genetic condition in which excess iron is absorbed by the intestine and deposited throughout the body [2]. If untreated, affected individuals may accumulate excess iron over the many years of their adult life, and this causes progressive tis- sue damage [3]. It has been reported that HH may result in many diseases, including liver disease (fibrosis, cirrho- sis, and hepatocellular carcinoma). Some studies reported that liver disease was the most common cause of death of patients with HH [4,5]. * Correspondence: shen.xizhong@zs-hospital.sh.cn Department of Gastroenterology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China In 1996, Feder and colleagues [6] showed that homo- zygosity for mutation (C282Y, G>A, rs1800562) in the HFE gene was responsible for the majority of cases of typical phenotypic HH. The frequency of the second variant (H63D, C>G, rs1799945) is also increased in HH patients, but its penetrance is low. From then on, HFE gene has been postulated as a candidate gene of HCC. Some studies [7-16] demonstrated that C282Y or H63D increased the risk of HCC, while some [17-19] gave negative results. Some large scale cohort studies [20,21] also showed that HFE gene mutation penetrance was low and did not increase the likelihood of death from any cause among the C282Y homozygotes compared with subjects who had no C282Y mutation. However, the estimates in these cohort studies were conservative in the sense that in the cohort study per- iod, a proportion of HH patients had received phlebot- omy treatment. As a result, the role of C282Y and © 2010 Jin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.