Hepcidin-based screening for infantile iron deficiency

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化科学和特定的挑战主题，15-DK-106：翻译基本血液学概念。该提案涉及在预防、诊断和治疗婴儿缺铁的方法中应用铁代谢激素hepcidin的新检测方法。缺铁性贫血（IDA）影响美国近3%的1-2岁儿童。至少有9%以上的人是非贫血，但缺铁（ID），并有神经发育缺陷的风险。虽然具体的建议各不相同，但联邦机构和专业实践协会一致建议儿科医生对婴儿进行ID筛查，通常在婴儿出生后第一年结束前。筛查方法也各不相同，但在每种情况下，都要在快速性、侵入性、成本、灵敏度和特异性之间做出妥协。毫不奇怪，最敏感的测试，网织红细胞的细胞血红蛋白（CHr），是最具侵入性和最昂贵的，而且，不是所有的自动血液学仪器。相反，成本最低，侵入性最小的测试，手指针刺血红蛋白，也是最不敏感的。此外，许多ID筛查测试不直接询问儿童的铁状态。由于容易纠正ID与膳食补充剂和必要性，以确定一个早期ID（EID）状态贫血发展之前，当儿童仍然处于神经系统后遗症的风险，存在迫切需要确定一个敏感的，具有成本效益的，快速的，微创的EID屏幕。该提案将评估一种新的测试，血清hepcidin，作为婴儿ID的屏幕。此外，使用相同的数据集，我们将解决编码TMPRSS 6（一种调节hepcidin产生的蛋白质）的基因中的变体可能使儿童在婴儿期易患某种形式的ID，这种ID可能不是口服铁补充剂最好的治疗方法。铁调素是一种在肝脏中产生的肽激素，主要是响应于铁储存。铁调素是全身铁代谢的中心调节剂。铁调素负调节铁从细胞，特别是十二指肠上皮细胞和巨噬细胞的流出，在十二指肠上皮细胞中，铁被吸收到体内，巨噬细胞从衰竭的RBC中回收铁。因此，对ID的适当生理反应是减少铁调素的产生以促进铁从肠吸收并从巨噬细胞释放储存的铁。血清铁调素水平现在可以用灵敏的酶联免疫吸附试验（ELISA）进行测量。初步研究表明，铁调素在缺铁成人的血清中显著降低或检测不到。此外，血清铁调素和血清铁蛋白之间存在直接关系，后者已被证明与铁储存相关。通过评估血清铁调素与铁储备的关系，特别是在婴儿人群中，特别是在ID和ID相关并发症的风险，我们应该能够确定与所有其他ID筛查方法相比，该测试的潜在优势或劣势。遗传缺陷，导致异常低水平的hepdicin生产响应身体铁储备的基础上的遗传性铁过载疾病统称为遗传性血色病的绝大多数情况下。最近，我们确定了双等位基因突变的肝脏特异性跨膜丝氨酸蛋白酶，TMPRSS 6，在个人的表型相反的遗传性血色素沉着症，一种疾病称为铁难治性ID贫血（IRIDA）。IRIDA患者患有ID，其由于铁调素表达的不适当增加而对口服和胃肠外铁补充剂无反应。此外，我们现在已经确定TMPRSS 6突变杂合子个体具有轻度不适当升高的铁调素水平。在人类群体中TMPRSS 6中存在几种常见和许多低频氨基酸变体（cSNP）。在这里，我们建议确定TMPRSS 6中的这些cSNPs与婴儿期ID风险之间是否存在关系。这可能是重要的，因为它可以识别在此期间ID风险最大的那些个体，并且可能指示他们被假定地治疗或与具有“常见”ID的那些个体不同。我们预期这些数据将1）确定铁调素是否具有用于婴儿群体中ID的常规评估的潜在临床价值，以及2）TMPRSS 6变体是否是婴儿ID的风险因素。最终，如果我们的假设是正确的，这项研究将为更好地筛查和管理ID奠定基础，不仅在这一人群中，而且在所有儿童和成人中。缺铁在婴儿期很常见，会导致贫血和发育迟缓。因此，建议所有儿童在婴儿期进行缺铁筛查。在这里，为了改善儿童的预防保健，我们将测试一种新的，可能更准确的血液筛查测试铁缺乏症的效用，并开始确定是否有遗传易感性，以铁缺乏症在婴儿期。 公共卫生相关性：缺铁在婴儿期很常见，可导致贫血和发育迟缓。因此，建议所有儿童在婴儿期进行缺铁筛查。在这里，为了改善儿童的预防保健，我们将测试一种新的，可能更准确的血液筛查测试铁缺乏症的效用，并开始确定是否有遗传易感性，以铁缺乏症在婴儿期。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Science and specific Challenge Topic, 15-DK-106: Translating Basic Hematology Concepts. The proposal involves the application of a novel assay for the iron metabolism hormone hepcidin in the approach to prevent, diagnose, and treat iron deficiency in infants. Iron deficiency anemia (IDA) affects nearly 3% of children in the U.S. aged 1-2 years. At least 9% more are non-anemic, but iron deficient (ID) and are at risk for neurodevelopmental deficits. Although the specific recommendations vary, Federal agencies and professional practice associations uniformly suggest that pediatricians screen infants for ID, typically before the end of the first year of life. The method of screening also varies, but, in each case, a compromise is made between the rapidity, invasiveness, cost, sensitivity, and specificity of the test. Not surprisingly, the most sensitive test, the cellular hemoglobin of the reticulocytes (CHr), is the most invasive and most costly, and, furthermore, is not available on all automated hematology instruments. Conversely, the least costly, least invasive test, the finger stick hemoglobin, is also the least sensitive. Furthermore, many ID screening tests do not directly interrogate the iron status of the child. Because of the ease of correcting ID with dietary supplements and the imperative to identify an early ID (EID) state before anemia develops, when children are nonetheless at risk for neurological sequelae, there exists a compelling need to identify a sensitive, cost-effective, rapid, minimally invasive screen for EID. This proposal will evaluate a new test, the serum hepcidin, as a screen for ID in infants. Furthermore, using the same dataset, we will address the possibility that variants in the gene encoding TMPRSS6, a protein that modulates hepcidin production, could predispose children to a form of ID in infancy that may not be best treated with oral iron supplements. Hepcidin is a peptide hormone produced in the liver largely in response to iron stores. Hepcidin is the central regulator of systemic iron metabolism. Hepcidin negatively regulates the egress of iron from cells, particularly duodenal intestinal epithelial cells, where iron is absorbed into the body, and macrophages, which recycle iron from effete RBCs. Thus, the appropriate physiological response to ID is to decrease hepcidin production to promote iron absorption from the intestine and release stored iron from macrophages. Serum hepcidin levels can now be measured with a sensitive enzyme-linked immunosorbent assay (ELISA). Initial studies have shown that hepcidin is markedly decreased or not detectable in the serum of iron deficient adults. Furthermore, there is a direct relationship between serum hepcidin and serum ferritin, the latter of which has been shown to correlate with iron stores. By evaluating the relationship of serum hepcidin to iron stores specifically in the infant population uniquely at risk for ID and ID-associated complications we should be able to determine the potential superiority or inferiority of this test in comparison to all other ID screening methodologies. Genetic defects that lead to abnormally low levels of hepdicin production in response to body iron stores underlie the vast majority of cases of the hereditary iron overload disorders collectively termed hereditary hemochromatosis. Recently, we identified biallelic mutations in the liver-specific transmembrane serine protease, TMPRSS6, in individuals with the phenotype opposite to hereditary hemochromatosis-a disorder termed iron refractory ID anemia (IRIDA). IRIDA patients have ID that is unresponsive to oral and parenteral iron supplementation due to inappropriately increased hepcidin expression. Furthermore, we have now determined that individuals heterozygous for TMPRSS6 mutations have mildly inappropriately elevated hepcidin levels. Several common and many low frequency amino acid variants (cSNPs) exist in TMPRSS6 in the human population. Here, we propose to determine if there is a relationship between these cSNPs in TMPRSS6 and the risk for ID in infancy. This is potentially important as it could identify those individuals at greatest risk for ID in this period and might dictate that they be treated presumptively or differently than those with "common" ID. We anticipate that these data will 1) determine if hepcidin is of potential clinical value for routine evaluation of ID in the infant population, and 2) whether TMPRSS6 variants are a risk factor for infantile ID. Ultimately, if our hypotheses are correct, this study will lay the foundation for better screening and management of ID, not only in this population, but in all children and adults alike. Iron deficiency is common in infancy and can lead to anemia as well as developmental delays. Consequently, it is recommended that all children be screened for iron deficiency in infancy. Here, in order to improve preventative care for children, we will test the utility of a new, potentially more accurate blood screening test for iron deficiency and begin to determine if there is a genetic susceptibility to iron deficiency in infancy. PUBLIC HEALTH RELEVANCE: Iron deficiency is common in infancy and can lead to anemia as well as developmental delays. Consequently, it is recommended that all children be screened for iron deficiency in infancy. Here, in order to improve preventative care for children, we will test the utility of a new, potentially more accurate blood screening test for iron deficiency and begin to determine if there is a genetic susceptibility to iron deficiency in infancy.