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Ethnic Differences in Iron Absorption

铁吸收的种族差异

基本信息

批准号：
10379297
负责人：
Kimberly O O'Brien
金额：
$ 53.98万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379297
关键词：
Address Affect Age Asian population Automobile Driving Biochemical Biological Biological Markers Blood Cardiomyopathies Chronic Disease Cirrhosis Data Dietary Iron Disease Disease susceptibility East Asian Erythropoietin European Excretory function Exhibits Future Gender Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Variation Genetic study Genome Genomics Geographic Distribution Goals Haplotypes Hematology Homeostasis Hormonal Hormones Human Human Genetics Individual Intake Iron Iron Isotopes Iron Overload Light Link Magnetism Malignant Neoplasms Mass Spectrum Analysis Measures Metabolic Metabolic Diseases Micronutrients Modeling Non-Insulin-Dependent Diabetes Mellitus Nutritional Participant Pathway interactions Phenotype Physiological Processes Play Policy Making Population Population Genetics Population Heterogeneity Positioning Attribute Predisposition Public Health Recommendation Regulation Role Route Site Testing Variant Woman absorption bead chip cohort dietary ethnic difference ethnic diversity exhaustion genetic architecture genetic variant genome wide association study genomic locus hepcidin in vivo interdisciplinary approach ionization iron absorption iron deficiency iron metabolism male metabolic abnormality assessment micronutrient deficiency novel nutrient metabolism nutrition racial diversity recruit risk minimization trait

项目摘要

Iron deficiency remains the most widespread micronutrient deficiency worldwide, whereas Fe overload has been increasingly appreciated as a contributor to many types of chronic disease, such as type II diabetes, cirrhosis, cancer and cardiomyopathy. We hypothesize that evolutionary adaptations in genes involved in non- heme Fe metabolism, in East Asian populations, have resulted in an increased efficiency of Fe absorption even in the face of adequate Fe stores. Our preliminary data from multiple GWA studies on blood Fe status in populations of European and/or East Asian genetic backgrounds, found novel and statistically significant enrichment for associations with Fe status in other genes that have been shown to regulate Fe via multiple biological pathways, suggesting a highly polygenic genetic architecture underlying Fe absorption and regulation in humans. The enrichment of associations of variations in these genes with blood Fe status at a pathway level implies that genetic variation affecting Fe absorption and regulation has yet to be exhaustively identified. We propose to employ a direct functional measure of an individuals' capacity to absorb and utilize non-heme Fe to build an unbiased genetic architecture of (non-heme) Fe utilization in humans. We are uniquely positioned to address genetic determinants of Fe homeostasis using a multidisciplinary approach. We will first undertake a functional study to investigate population differences in non-heme Fe absorption in a large cohort of East Asians (n=252) and Northern Europeans (n=252). Population differences in Fe absorption will be evaluated in relation to a fixed level of Fe stores (Aim 1). Three hormones, hepcidin, erythroferrone and erythropoietin, are now known to regulate systemic Fe homeostasis. In Aim 2, we will characterize these hormones and additional hematological, and Fe status biomarkers in all 502 participants to develop models to investigate variability in Fe absorption that can be captured by existing Fe biomarkers and regulatory hormones as a function of age, gender and population. To fully capture known and novel genetic variations underlying Fe absorption in different populations, genetic variants will be measured in all 504 participants in Aim 1 using the Illumina Infinium BeadChip. We will investigate the genetic contribution to Fe absorption, Fe status and Fe regulatory hormones and explore possible differences as a function of genetically confirmed ancestry (Aim 3). Our approach thus has the potential to identify novel relevant Fe homeostatic pathways that are associated with Fe status and more importantly that may be driving variability in Fe absorption, the key regulatory site of Fe homeostasis. These studies will provide novel information on human dietary adaptation that will shed light on the genetic basis of population discrepancy in traits and disease susceptibility, and will guide future genome-informed nutritional practices.

铁缺乏仍然是世界范围内最普遍的微量营养素缺乏症，而铁超载则是越来越多地被认为是许多类型慢性疾病的贡献者，如II型糖尿病，肝硬化癌症和心肌病我们假设，基因的进化适应涉及非- 在东亚人群中，血红素铁代谢导致铁吸收效率增加即使有足够的铁储备。我们的初步数据来自多项GWA研究，欧洲和/或东亚遗传背景人群，发现新的和统计学显著性富集与其他基因中的Fe状态相关，这些基因已被证明通过多种途径调节Fe 生物学途径，这表明一个高度多基因遗传结构的铁吸收，人类的规则。这些基因的变异与血铁状态之间的关联在一定程度上是丰富的。途径水平表明，影响铁吸收和调节的遗传变异尚未被详尽地鉴定我们建议采用一种直接的功能性措施，衡量个人的吸收和利用非血红素铁建立一个公正的遗传结构的（非血红素）铁利用在人类。我们独特的定位，以解决铁稳态的遗传决定因素，使用多学科的方法。我们将首先进行功能性研究，以调查在非血红素铁吸收的人口差异，在一个大的东亚人（n=252）和北方欧洲人（n=252）队列。铁吸收的人口差异将相对于固定水平的铁存储（目标1）进行评估。三种激素，hepcidin，erythroferrone和促红细胞生成素，现在已知调节全身Fe稳态。在目标2中，我们将描述这些激素和其他血液学和铁状态生物标志物，以开发模型，研究可以通过现有Fe生物标志物和调节剂捕获的Fe吸收的变化荷尔蒙与年龄、性别和人口的关系为了充分捕捉已知的和新的遗传变异为了研究不同人群的铁吸收，将在所有504名参与者中测量遗传变异，目标1使用Illumina Infinium BeadChip。我们将研究遗传因素对铁吸收的影响，状态和铁调节激素，并探讨可能的差异作为一个功能的遗传证实祖先（目标3）。因此，我们的方法有可能确定新的相关铁稳态途径，与铁的状态有关，更重要的是，这可能是驱动铁吸收的变化，铁稳态的调节位点。这些研究将为人类饮食适应提供新的信息这将揭示性状和疾病易感性的群体差异的遗传基础，并将指导未来的基因组知情营养实践。