Human Requirements for the Nutrient Choline

描述（由申请人提供）：胆碱是一种对细胞膜的结构完整性和信号传导功能至关重要的膳食营养素;它是膳食中甲基的主要来源，并直接影响胆碱能神经传递、跨膜信号传导和脂质转运/代谢。这一建议的主要前提是，人类需要胆碱的饮食来源，这种需求具有显着的个体差异。我们认为，雌激素和常见的遗传多态性调节胆碱的饮食需求。在过去4年的资助中，我们确定了77%的男性和80%的绝经后女性，当被剥夺饮食胆碱时，会发生脂肪肝或肌肉损伤。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体征。一些男性在摄入假定的胆碱充足摄入量（550 mg/天）时出现胆碱缺乏症的症状。我们观察到PEMT启动子是雌激素反应性的，我们假设雌激素状态影响胆碱的饮食需求。我们发现了常见的遗传变异，这些变异似乎增加了人类在摄入低胆碱饮食时胆碱缺乏的可能性;绝经后妇女在负责胆碱内源性生物合成的基因启动子区具有常见的单核苷酸多态性（snp），（磷脂酰乙醇胺N-甲基转移酶，PEMT; rs 12325817）与野生型相比，当我们从他们的饮食中去除胆碱时，发生器官功能障碍的迹象的比值比（OR）为42（p=0.03）;在胆碱脱氢酶中具有G78 T单核苷酸多态性的绝经前妇女发生胆碱缺乏症的OR为20（p=0.04），而在亚甲基四氢叶酸脱氢酶（MTHFD 1 - 1958 A）中具有普通单核苷酸多态性的绝经前妇女发生胆碱缺乏症的OR>85（p= 0.0001）。我们在胆碱脱氢酶A40中发现了另一个SNP，该SNP与所有受试者中出现胆碱缺乏症状的易感性降低相关（OR = 0.2; p = 0.03）。这些SNP在人类中很常见，例如，对于PEMT启动子SNP，我们的受试者中18%为SNP纯合型，56%为杂合型，26%为野生型。因此，重要的是，我们有一个更好地了解这些遗传多态性如何影响胆碱的饮食需求。我们提出的研究将延长我们在最后一个资助期间的观察，并将完善我们对影响人类胆碱饮食需求的因素的理解。实验提出，将确定是否绝经后妇女与雌激素治疗有较低的胆碱需求，确定功能上重要的SNP，确定这些在人群中的患病率，并检查这些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.