Serum Biomarkers Associated With Phenotypic Expression of Hemochromatosis.

描述(申请人提供)：遗传性血色沉着症(HH)是一种常染色体隐性遗传性疾病，以肝脏铁的进行性积累为特征，是高加索人中最常见的遗传病之一，估计发病率为1/250，在白人人群中的杂合子携带率为8%？10%。如果不治疗不可逆转的器官损伤，心肌病、糖尿病、肝硬变和肝细胞癌可能发生在生命的第四个或第五个十年。几乎所有的血色沉着症都是由于HFE基因的纯合错义突变所致，该基因将氨基酸残基282从半胱氨酸改变为酪氨酸(C282Y)。然而，该突变只有部分外显性，许多C282Y纯合子没有症状。完全的临床外显性，如明显的器官损害，要少得多，可能取决于种族、环境或遗传因素。一个或多个疾病修饰基因的存在已被假设，但尚未得到证实。MicroRNAs(MiRNAs)是一种小的非编码RNA，通过与信使RNAs(Messenger RNAs)3‘非翻译区的部分互补靶序列配对来促进mRNA降解和/或阻止翻译，从而负向调节基因的表达。近年来的研究表明，多种肝病及肝细胞癌、乙肝病毒和肝硬变患者的血清miRNA水平均升高，因此，血清miRNA是一种新型的诊断和预后生物标志物，也是多种肝病潜在的治疗靶点。MiRNAs在HH中的作用尚不清楚，尽管最近有研究表明，肝脏特异的miRNAmiR-122通过在小鼠血色病模型中抑制海普西丁及其激活物、HFE和Hjv基因的表达，参与了哺乳动物的铁稳态。我们提出了一种多方面的方法来确定新的血清生物标志物、血清海普西丁水平和miRNA基因表达谱，这些基因表达谱是潜在的铁稳态调节机制的基础。建议的研究是可行的，将利用继承人研究的大量资源，并将提供一个独特的机会来确定涉及C282Y HFE突变外显性的新机制。

DESCRIPTION (provided by applicant): Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by a progressive accumulation of hepatic iron and is one of the most common inherited diseases among Caucasians with an estimated prevalence of 1 in 250 and a heterozygote carrier rate of 8%¿10% in the white population. If left untreated irreversible organ damage, cardiomyopathy, diabetes mellitus, cirrhosis and hepatocellular carcinoma can occur in the 4th or 5th decade of life. Nearly all cases of hemochromatosis are due to a homozygous missense mutation in the HFE gene that changes amino acid residue 282 from a cysteine to a tyrosine (C282Y). However, there is only partial penetrance of this mutation and many C282Y homozygotes are asymptomatic. Full clinical penetrance, such as marked organ damage, is much less common and may depend on ethnic, environmental or genetic factors. The presence of one or more disease modifying genes has been postulated but has yet to be proven. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3' untranslated regions of messenger RNAs (mRNAs) to promote mRNA degradation and/or block translation. Recent studies have shown that levels of many circulating serum miRNA are elevated in patients with a variety of liver diseases and pathologies including HCC, HBV and liver cirrhosis, therefore serum miRNAs represent a new type of diagnostic and prognostic biomarker, and potential therapeutic target for several liver diseases. The role of miRNAs in HH is uncharacterized, although a liver specific miRNA miR-122 was recently shown to be involved in mammalian iron homeostasis by repressing the expression of hepcidin and its activators, the Hfe and Hjv genes in a mouse model of hemochromatosis. We are proposing a multifaceted approach to identify novel serum biomarkers, serum hepcidin levels and miRNA gene expression profiles that underlie potential iron homeostasis regulatory mechanisms. The proposed studies are feasible, will harness the vast resources of the HEIRS Study and will provide a unique opportunity to determine novel mechanisms involved in the penetrance of the C282Y HFE mutation.