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

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. gene controls the iron uptake from gut, particularly in patients with hereditary hemochromatosis (HH).

Aim: To identify associations between 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 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 gene was performed using the Haploview software.

Results: The *003 allele was overrepresented ( = 71%) and *001 allele was underrepresented ( = 14%) in HH patients compared to all groups. A strong linkage disequilibrium was observed among the , and gene variants, particularly in HH; however, the mutation was not directly associated with HH susceptibility. The *001/*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO ( = 0.02, OR = 14.14). Although is telomeric to other histocompatibility genes, the ( ≤ 0.00001/ ≤ 0.0057) combination was in LD with *44 allele group in healthy controls. No LD was observed between alleles and other major histocompatibility loci.

Conclusion: A differential association was observed for HH and for diseases associated with acquired IO (HCV, HCC). Since is very distant from other histocompatibility loci, only weak associations were observed with these alleles.