Ethnic Differences in Iron Absorption

铁缺乏仍然是世界上最普遍的微量营养素缺乏症，而铁超载则 越来越多的人认识到，这是导致许多类型的慢性病的因素，如II型糖尿病， 肝硬变、癌症和心肌病。我们假设，基因的进化适应涉及非 东亚人群中的血红素铁代谢导致铁吸收效率的提高 即使面对充足的Fe商店。我们从多项GWA研究中获得的初步数据 欧洲和/或东亚遗传背景的人群，发现了新的和统计上有意义的 富集与铁状态相关的其他基因，这些基因已被证明通过多个 生物学途径，暗示了铁吸收和铁吸收的高度多基因遗传结构 对人类的监管。这些基因变异与老年人血铁状态的相关性研究 途径水平表明，影响铁吸收和调节的遗传变异尚未穷尽 已确认身份。我们建议采用一种直接的功能衡量方法来衡量个人吸收和 利用非血红素铁在人类中建立(非血红素铁)利用的无偏见遗传架构。我们是 独特的定位，利用多学科方法解决铁稳态的遗传决定因素。我们 将首先进行一项功能研究，以调查人群在非血红素铁吸收方面的差异 东亚人(n=252)和北欧人(n=252)。铁吸收的种群差异将 根据一个固定的铁储存水平进行评估(目标1)。三种激素，海普西丁，红铁酮和 促红细胞生成素，现在已知调节全身铁的动态平衡。在目标2中，我们将描述这些特性 所有502名参与者的激素和额外的血液学和铁状态生物标记物，以建立模型 研究现有铁生物标志物和调节因子可捕获的铁吸收的变异性 荷尔蒙是年龄、性别和人口的函数。全面捕捉已知和新的基因变异 根据不同人群的铁吸收情况，将在所有504名参与者中测量遗传变异 目标1使用Illumina Infinium珠片。我们将研究基因对铁吸收的贡献，铁 状态和铁调节激素，并探索作为遗传确认的功能的可能差异 血统(目标3)。因此，我们的方法有可能识别新的相关铁稳态途径， 与铁的状况有关，更重要的是，这可能是铁吸收的变化，这是关键 铁稳态的调节部位。这些研究将为人类饮食适应提供新的信息。 这将阐明种群特征差异和疾病易感性的遗传基础，并将 指导未来的基因组信息营养实践。

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.