Hepcidin-based screening for infantile iron deficiency

描述（由申请人提供）：该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。该提案涉及应用一种新的检测铁代谢激素hepcidin的方法来预防、诊断和治疗婴儿缺铁。缺铁性贫血（IDA）影响了美国近3%的1-2岁儿童。至少9%以上的人没有贫血，但缺铁（ID），有神经发育缺陷的风险。尽管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，通常是在一岁之前。筛查的方法也各不相同，但在每种情况下，都要在快速、侵入性、成本、敏感性和特异性之间做出妥协。毫不奇怪，最敏感的测试，网状红细胞的细胞血红蛋白（CHr），是最具侵入性和最昂贵的，而且，并不是所有的自动化血液学仪器都可以使用。相反，成本最低、侵入性最小的测试——指棒血红蛋白测试——也是最不敏感的。此外，许多身份证筛选测试并不直接询问儿童的铁状况。由于通过膳食补充剂纠正ID很容易，并且在贫血发生之前确定早期ID （EID）状态的必要性，当儿童仍有神经系统后遗症的风险时，迫切需要确定一种敏感、经济、快速、微创的EID筛查方法。本提案将评估一种新的测试，血清hepcidin，作为婴儿ID的筛查。此外，使用相同的数据集，我们将解决编码TMPRSS6（一种调节hepcidin产生的蛋白质）的基因变异可能使儿童在婴儿期易患某种形式的ID，而口服铁补充剂可能不是最好的治疗方法。Hepcidin是一种肽激素，在肝脏中产生，主要是对铁储存的反应。Hepcidin是全身铁代谢的中枢调节因子。Hepcidin负向调节铁从细胞的输出，特别是十二指肠肠上皮细胞，铁被吸收到体内，以及巨噬细胞，从失效的红细胞中回收铁。因此，对ID的适当生理反应是减少hepcidin的产生，以促进肠道对铁的吸收，并释放巨噬细胞中储存的铁。血清hepcidin水平现在可以用灵敏的酶联免疫吸附试验（ELISA）来测量。初步研究表明，hepcidin在缺铁成人血清中明显降低或检测不到。此外，血清hepcidin和血清铁蛋白之间存在直接关系，后者已被证明与铁储存有关。通过评估血清hepcidin与铁储存的关系，特别是在具有ID和ID相关并发症风险的婴儿人群中，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。大多数遗传性铁超载疾病统称为遗传性血色素沉着症，遗传缺陷导致机体铁储存异常低水平的hepdicin产生。最近，我们在与遗传性血色素病（一种称为铁难耐性ID性贫血（IRIDA）的疾病）表型相反的个体中发现了肝脏特异性跨膜丝氨酸蛋白酶TMPRSS6的双等位基因突变。IRIDA患者由于不适当地增加hepcidin表达而对口服和肠外补铁无反应。此外，我们现在已经确定，TMPRSS6突变的杂合个体有轻度不适当的hepcidin水平升高。人类TMPRSS6中存在几种常见和许多低频氨基酸变异（csnp）。在这里，我们建议确定TMPRSS6中的这些csnp与婴儿期ID风险之间是否存在关系。这可能很重要，因为它可以识别出这一时期ID风险最大的个体，并可能规定他们被推定或区别于“普通”ID的人。我们预计这些数据将1)确定hepcidin是否对婴儿人群中ID的常规评估具有潜在的临床价值，以及2)TMPRSS6变异是否是婴儿ID的危险因素。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都是如此。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，为了改善对儿童的预防性护理，我们将测试一种新的、可能更准确的铁缺乏血液筛查试验的效用，并开始确定婴儿是否有铁缺乏的遗传易感性。

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.