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
HFE gene controls the iron uptake from gut, and defects of the encoded molecule have been associated with iron overload (IO), particularly in hemochromatosis hereditary (HH), which can cause serious damage to the liver. Besides HH, patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may or not develop IO.
The search for markers associated with IO may be very useful for the early diagnosis of these patients, which is essential for their survival.
The main objectives of this work is to identify associations between HFE coding region variable sites in patients exhibiting HH and in diseases associated with acquired IO.
We sequenced exons 2 to 5 and boundary introns of the HFE gene to evaluate all polymorphic sites in patients presenting HH or acquired IO (HCV and HCC), and in healthy controls, using Sanger sequencing. We also determined the extended haplotype in healthy controls, including other major histocompatibility genes (HLA-A/-B/-C/-DRB1/-DQB1 alleles, and HLA-G 14bp INDEL and TNFa-d microsatellites). 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 LD was observed among the previously reported H63D-G, IVS2(+4)-C and C282Y-G gene variants, particularly in HH; however, the mutation IVS2(+4)T>C was not 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.
This study systematically evaluated variation sites along the HFE gene using the HLA official nomenclature, previously described by our group. The HFE*003 allele that was overrepresented in HH patients encompasses major variation sites previously described in association with HH in several worldwide populations, in contrast with the HFE*001 allele which does not present HH-associated variation sites and predominates among healthy controls. On the other hand, the HFE*001/HFE*002 genotype was identified as a risk factor for HCC and HCV patients exhibiting IO. Although the HFE gene is distant from other histocompatibility genes, the HFE H63D-G/IVS2(+4)-C alleles were in weak LD with the HLA-B*44 allele. Thus, a differential HFE association was observed for HH and for diseases associated with acquired IO (HCV, HCC).
Besides the identification of markers associated with IO, which may permit an early detection of patients prone to develop iron deposits, the knowledgement of the major gene associated with iron uptake may help on the understanding of the IO pathogenesis.