Comprehensive analysis ofHFEgene in hereditary hemochromatosis and in diseases associated with acquired iron overload

Abstract

BACKGROUND 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). AIM To identify associations between HFE coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO. METHODS 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. RESULTS 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. CONCLUSION 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.

Polymorphisms Related to Iron Homeostasis Associate with Liver Disease in Chronic Hepatitis C

“…In our study, carriers of two dominant alleles in H63D rs1799945 were less frequently diagnosed with hepatic iron overload ( Table 1 ). The role of HFE mutations in secondary iron overload diagnosed in CHC still remains unclear, as some studies show association H63D and C282Y mutations with elevated serum iron indices [ 19 , 29 ], liver iron deposits [ 11 ], and others reported no such relation [ 6 , 30 ]. Our results confirm the notion that HFE mutations may contribute to (but do not fully explain) hepatic iron accumulation in chronic hepatitis C.…”

“…The most common mutations, responsible for the majority of hemochromatosis cases in patients with East European ancestry, are mutations in the coding region of HFE gene: C282Y rs1800562, H63D rs1799945, and S65C rs1800730. The penetrance of these mutations is modulated by other genetic polymorphisms and unknown factors [ 6 ]. The rs855791 C > T mutation in TMPRSS6 gene encoding transmembrane serine protease matriptase-2, which cleaves multiple proteins from HFE and Bmp6 signaling pathways, reduces enzyme proteolytic activity.…”

The Roles and Pathogenesis Mechanisms of a Number of Micronutrients in the Prevention and/or Treatment of Chronic Hepatitis, COVID-19 and Type-2 Diabetes Mellitus

“…This was suggested to have a contribution to the release of the cytokine, which triggers liver inflammation and fibrosis [94]. Other studies have focused on the role of the hemochromatosis gene (HFE) on the cellular level and have concluded that it promotes iron (Fe) overload in patients with HCV infection [96].…”