Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls

PLOS ONE, Dec 2019

Background Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). Methods An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. Results In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation<0.05). However, no significant difference between liver cirrhosis cases and the control group was observed for HFE C282Y and H63D (all Passociation>0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed. Conclusion Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0163423&type=printable

Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls

D Polymorphisms and the Risks of Non- Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non- Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls Qing Ye 0 1 Bao-Xin Qian 0 1 Wei-Li Yin 0 1 Feng-Mei Wang 0 1 Tao Han 0 1 0 The Third Central clinical college of Tianjin Medical University , Tianjin , PR China , 2 Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital , Tianjin , PR China , 3 Tianjin Institute of Hepatobiliary Disease , Tianjin , PR China , 4 Tianjin Key Laboratory of Artificial Cells , Tianjin , PR China 1 Editor: Pavel Strnad , Medizinische Fakultat der RWTH Aachen , GERMANY - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This study was supported by Tianjin Science and Technology Fund, China (no. 13RCGFSY19200). Competing Interests: The authors have declared that no competing interests exist. Background Methods Results Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). An updated systematic review and meta-analysis was conducted to evaluate the poten tial role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation<0.05). However, no significant difference between liver cirrhosis cases and the control group was observed for HFE C282Y and H63D (all Passociation>0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed. Conclusion Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion. Introduction Hepatocellular carcinoma (HCC) often occurs as the end-stage or more aggressive form of many progressive chronic liver diseases, such as NAFLD (non-alcoholic fatty liver disease), liver cirrhosis, and chronic viral hepatitis [ 1–4 ]. NAFLD is a series of chronic liver disease with fat deposition in the absence of significant alcohol consumption, including simple fatty liver, NASH (non-alcoholic steatohepatitis), liver fibrosis and cirrhosis [ 5, 6 ]. Liver cirrhosis is a common clinical chronic liver injury that is characterized by the formation of microscopic or macroscopic nodules separated by bands of fibrous tissue, impairment of hepatocellular function, and obstruction of portal circulation [ 3, 4 ]. There are many types of liver cirrhosis, such as cryptogenic cirrhosis, alcoholic liver cirrhosis, viral liver cirrhosis and NAFLD-associated cirrhosis, which are considered as the key risk factors for the occurrence of HCC [ 3–8 ]. Various polymorphisms of genes, such as patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member (TM6SF2) 2 and methylenetetrahydrofolate reductase (MTHFR), are involved in susceptibility to the above liver diseases [ 9–16 ]. Human hereditary hemochromatosis (HFE) gene, first identified by Feder JN et al. in 1996, is located on the short arm of chromosome 6 (6p21.3) [ 17 ]. The HFE gene encodes a 343-amino acid glycoprotein (HFE protein), a member of the major histocompatibility complex class I-like family [ 17, 18 ]. As a key component of iron homeostasis in humans, the HFE protein is linked to the incidence of hereditary hemochromatosis (HH), an autosomal recessive disorder [ 17, 18 ]. Several common polymorphisms of the HFE gene, such as C282Y (rs1800562), H63D (rs1799945) and S65C (rs1800730), have been reported [ 18, 19 ]. Accumulating evidence indicates that HFE mutations are associated with susceptibility to many clinical diseases, such as Parkinson' (...truncated)


This is a preview of a remote PDF: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0163423&type=printable

Qing Ye, Bao-Xin Qian, Wei-Li Yin, Feng-Mei Wang, Tao Han. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls, PLOS ONE, 2016, Volume 11, Issue 9, DOI: 10.1371/journal.pone.0163423