Published online Feb 27, 2019. doi: 10.4254/wjh.v11.i2.186
Peer-review started: December 10, 2018
First decision: January 5, 2019
Revised: January 17, 2019
Accepted: January 26, 2019
Article in press: January 26, 2019
Published online: February 27, 2019
Patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may or not develop iron overload (IO), which is associated with worst prognosis, because can cause serious damage to organs. HFE gene controls the iron uptake from gut, particularly in patients with hereditary hemochromatosis (HH).
To identify associations between HFE coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.
We sequenced exons 2 to 5 and boundary introns of HFE gene, evaluating all polymorphic sites in patients presenting hereditary (hemochromatosis) or acquired iron overload HCV and HCC) and in healthy controls, using Sanger sequencing. We also determined the ensemble of extended haplotype in healthy control individuals, including several major histocompatibility complex loci, using sequence specific probes. Haplotype reconstruction was performed using the Arlequin and Phase softwares, and linkage disequilibrium (LD) between histocompatibility loci and HFE gene was performed using the Haploview software.
The HFE*003 allele was overrepresented (f = 71%) and HFE*001 allele was underrepresented (f = 14%) in HH patients compared to all groups. A strong linkage disequilibrium was observed among the H63D-G, IVS2(+4)-C and C282Y-G gene variants, particularly in HH; however, the mutation IVS2(+4)T>C was not directly associated with HH susceptibility. The HFE*001/HFE*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO (P = 0.02, OR = 14.14). Although HFE is telomeric to other histocompatibility genes, the H63D-G/IVS2(+4)-C (P ≤ 0.00001/P ≤ 0.0057) combination was in LD with HLA-B*44 allele group in healthy controls. No LD was observed between HFE alleles and other major histocompatibility loci.
A differential HFE association was observed for HH and for diseases associated with acquired IO (HCV, HCC). Since HFE is very distant from other histocompatibility loci, only weak associations were observed with these alleles.
Core tip: Patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may or not develop iron overload (IO), which is associated with worset prognosis. The sequencing of the HFE gene permitted to assemble the previously described variation sites (H63DC>G-, S65CA>T and C282YG>A) associated with hereditary hemochromatosis into HFE haplotypes, under the standardized HLA nomenclature. A differential association of HFE alleles was observed for hereditary and acquired IO (HCV, HCC). In addition to the HFE gene, we also typed other major histocompatibility loci (HLA-A/-B/-C/ DRB1/-DQB1, and HLA-G 14bp INDEL and TNFa-d microsatellites) in the healthy population to understand how the HFE gene variability is associated with these loci.