Comprehensive analysis of HFE gene in hereditary hemochromatosis and in diseases associated with acquired iron overload

• 作者: Aguinaldo Luiz Simoes Ana de Lourdes Candolo Martinelli Andreza Correa Teixeira Celso Teixeira Mendes-Junior Cláudia Emília Vieira Wiezel Eduardo Antonio Donadi Eduardo Luiz Rachid Cancado Fernanda Fernandes de Souza Juliana Doblas Massaro Wagner Narciso de Campos
• 来源期刊: 世界肝病学杂志:英文版(电子版)
• 学科: 医学
• 关键词: HFE gene HEPATOCELLULAR carcinoma HEPATITIS C HEMOCHROMATOSIS HEREDITARY Alleles Haplotypes
• 年，卷（期）: 2019,（2）
• 页码范围: 186-198
• 页数: 13页
• 分类号: R

摘要

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 C282YG 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 H63DG/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.