Serum Biomarkers Associated With Phenotypic Expression of Hemochromatosis.

描述（由申请人提供）：遗传性血色病（HH）是一种常染色体隐性遗传疾病，其特征为肝脏铁的进行性蓄积，是高加索人中最常见的遗传性疾病之一，估计患病率为1/250，白色人群中杂合子携带率为8%至10%。如果不及时治疗，不可逆的器官损伤，心肌病，糖尿病，肝硬化和肝细胞癌可能发生在第四或第五个十年的生活。几乎所有血色素沉着症的病例都是由于HFE基因中的纯合错义突变，其将氨基酸残基282从半胱氨酸变为酪氨酸（C282 Y）。然而，这种突变只有部分突变，许多C282 Y纯合子无症状。完全的临床表现，如明显的器官损伤，是不太常见的，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定，但尚未得到证实。 MicroRNA（miRNAs）是一类小的非编码RNA，通过与信使RNA（mRNAs）3'端非翻译区部分互补的靶序列配对，促进mRNA降解和/或阻断mRNA翻译，从而负调控基因表达。近年来的研究表明，在包括HCC、HBV和肝硬化在内的多种肝脏疾病和病理过程中，许多循环血清miRNA水平升高，因此血清miRNA代表了一种新型的诊断和预后生物标志物，也是多种肝脏疾病的潜在治疗靶点。尽管最近在血色病小鼠模型中发现肝脏特异性miRNA miR-122通过抑制铁调素及其激活剂Hfe和Hlc基因的表达参与哺乳动物铁稳态，但miRNA在HH中的作用尚未表征。我们提出了一个多方面的方法来确定新的血清生物标志物，血清hepcidin水平和miRNA基因表达谱，潜在的铁稳态调节机制的基础。拟议的研究是可行的，将利用HEIRS研究的大量资源，并将提供一个独特的机会，以确定涉及C282 Y HFE突变的新机制。

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.