de Campos Wagner Narciso, Massaro Juliana Doblas, Cançado Eduardo Luiz Rachid, Wiezel Cláudia Emília Vieira, Simões Aguinaldo Luiz, Teixeira Andreza Correa, de Souza Fernanda Fernandes, Mendes-Junior Celso Teixeira, Martinelli Ana de Lourdes Candolo, Donadi Eduardo Antônio
Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil.
Department of Gastroenterology, Clinical Gastroenterology and Clinical Hepatology of Clinical Hospital, University of São Paulo School of Medicine, São Paulo 01329-000, Brazil.
World J Hepatol. 2019 Feb 27;11(2):186-198. doi: 10.4254/wjh.v11.i2.186.
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).
To identify associations between coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.
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.
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.
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.
丙型肝炎病毒（HCV）和肝细胞癌（HCC）患者可能会或不会发生铁过载（IO），铁过载与较差的预后相关，因为它会对器官造成严重损害。基因控制肠道对铁的吸收，特别是在遗传性血色素沉着症（HH）患者中。
确定遗传性血色素沉着症患者以及与获得性铁过载相关疾病中编码区之间的关联。
我们对基因的外显子2至5和边界内含子进行了测序，使用桑格测序法评估遗传性（血色素沉着症）或获得性铁过载（HCV和HCC）患者以及健康对照中的所有多态性位点。我们还使用序列特异性探针确定了健康对照个体中扩展单倍型的整体情况，包括几个主要组织相容性复合体基因座。使用Arlequin和Phase软件进行单倍型重建，并使用Haploview软件进行组织相容性基因座与基因之间的连锁不平衡（LD）分析。
与所有组相比，HH患者中003等位基因的比例过高（= 71%），而001等位基因的比例过低（= 14%）。在、和基因变体之间观察到强烈的连锁不平衡，特别是在HH中；然而，突变与HH易感性没有直接关联。*001/002基因型使表现出铁过载的HCV患者易患HCC（= 0.02，OR = 14.14）。尽管与其他组织相容性基因位于端粒，但在健康对照中，（≤ 0.00001/≤ 0.0057）组合与44等位基因组处于LD状态。在等位基因与其他主要组织相容性基因座之间未观察到LD。
在HH以及与获得性铁过载相关的疾病（HCV、HCC）中观察到不同的关联。由于与其他组织相容性基因座距离很远，与这些等位基因仅观察到弱关联。
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