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)