Human Requirements for the Nutrient Choline

描述（由申请人提供）：胆碱是一种对细胞膜结构完整性和信号功能至关重要的膳食营养素；它是日粮中甲基的主要来源，直接影响胆碱能神经传递、跨膜信号和脂质转运/代谢。这一建议的主要前提是人类需要从饮食中获取胆碱，而这种需求存在显著的个体差异。我们认为雌激素和常见的遗传多态性调节了这种对胆碱的饮食需求。在过去4年的资助中，我们发现77%的男性和80%的绝经后女性，当饮食中缺乏胆碱时，会患上脂肪肝或肌肉损伤。只有43%的绝经前妇女出现与胆碱缺乏相关的器官功能障碍的迹象。一些男性在摄入了假定的足够的胆碱摄入量（550毫克/天）后，出现了胆碱缺乏的迹象。我们观察到ppt启动子对雌激素有反应，我们假设雌激素状态会影响饮食对胆碱的需求。我们发现了常见的基因变异，这些变异似乎增加了人类在摄入低胆碱饮食时出现胆碱缺乏的可能性；在内源性胆碱生物合成基因（磷脂酰乙醇胺n -甲基转移酶，ppt, rs12325817）启动子区域具有常见单核苷酸多态性（snp）的绝经后妇女，当我们从她们的饮食中去除胆碱时，与野生型相比，出现器官功能障碍迹象的优势比（OR）为42 (p=0.03)；绝经前妇女胆碱脱氢酶G78T snp的OR值为20 (p=0.04)，绝经前妇女亚甲基四氢叶酸脱氢酶（MTHFD1-1958A）常见snp的OR值为bbb85 （p= 0.0001）。我们在所有受试者中发现了胆碱脱氢酶A40的另一个snp，该snp与发生胆碱缺乏迹象的易感性降低相关（OR = 0.2; p = 0.03）。这些snp在人类中很常见，例如，对于ppt启动子snp， 18%的受试者为纯合子，56%为杂合子，26%为野生型。因此，我们有更好地了解这些遗传多态性如何影响胆碱的饮食需求是很重要的。我们提出的研究将扩展我们在上一个资助期的观察，并将完善我们对影响人类胆碱饮食需求的因素的理解。实验将确定绝经后接受雌激素治疗的妇女是否有较低的胆碱需求，确定功能上重要的snp，确定这些snp在人群中的患病率，并检查具有这些snp的人的饮食胆碱需求。

DESCRIPTION (provided by applicant): Choline is a dietary nutrient essential for the structural integrity and signaling functions of cell membranes; it is the major source of methyl-groups in the diet, and it directly affects cholinergic neurotransmission, transmembrane signaling and lipid transport/metabolism. The major premise for this proposal is that humans require a dietary source of choline and that this requirement has significant individual variation. We suggest that estrogen and common genetic polymorphisms modulate this dietary requirement for choline. During the last 4 years of funding we established that 77% of men and 80% of postmenopausal women, when deprived of dietary choline, developed fatty liver or muscle damage. Only 43% of premenopausal women developed signs of organ dysfunction associated with choline deficiency. Some men developed such signs of choline deficiency when ingesting the presumed Adequate Intake for choline (550 mg/day). We observed that the PEMT promoter is estrogen responsive, and we hypothesize that estrogen status influences the dietary requirement for choline. We identified common genetic variations that appear to increase the likelihood that a human will become choline deficient when fed a low choline diet; postmenopausal women with a common single nucleotide polymorphism (snp) in the promoter region of the gene responsible for endogenous biosynthesis of choline (phosphatidylethanolamine N-methyltransferase, PEMT; rs12325817) had a odds ratio (OR) compared to wild type of 42 for developing signs of organ dysfunction when we removed choline from their diets (p=0.03); premenopausal women with a G78T snp in choline dehydrogenase had an OR of 20 (p=0.04) and premenopausal women with a common snp in methylene tetrahydrofolate dehydrogenase (MTHFD1-1958A) had an OR of >85 (p=.0001) for developing signs of choline deficiency. We identified another snp in choline dehydrogenase A40 that was associated with a decreased susceptibility to developing signs of choline deficiency in all subjects (OR = 0.2; p = 0.03). These snps are common in humans, for example, for the PEMT promoter snp 18% of our subjects were homozygous for the snp, 56% were heterozygous, and 26% were wild type. Therefore, it is important that we have a better understanding of how these genetic polymorphisms influence the dietary requirement for choline. We propose studies that will extend our observations during the last funding period and that will refine our understanding of factors that influence dietary requirements for choline in humans. Experiments are proposed that will determine whether postmenopausal women treated with estrogen have a lower choline requirement, identify functionally important SNPs, determine prevalence of these in the population and examine dietary choline requirements in humans with these SNPs.