Human Requirements for the Nutrient Choline

说明(申请人提供)：胆碱是一种膳食营养素，对细胞膜的结构完整性和信号功能是必不可少的；它是饮食中甲基的主要来源，它直接影响胆碱能神经传递、跨膜信号传递和脂质运输/代谢。这一提议的主要前提是，人类需要一种胆碱的饮食来源，而且这一要求具有显着的个体差异。我们认为雌激素和常见的基因多态调节了胆碱的这种饮食需求。在过去4年的研究中，我们发现77%的男性和80%的绝经后女性，当饮食中没有胆碱时，会发生脂肪肝或肌肉损伤。只有43%的绝经前女性出现与胆碱缺乏相关的器官功能障碍迹象。一些男性在摄入假定的足够胆碱摄入量(550毫克/天)时出现了胆碱缺乏的迹象。我们观察到PEMT启动子是雌激素反应的，我们假设雌激素状态影响胆碱的饮食需求。我们确定了常见的基因变异，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；绝经后女性在负责内源性胆碱生物合成的基因(磷脂酰乙醇胺N-甲基转移酶，PEMT；rs12325817)的启动子区具有常见的单核苷酸多态(SNP)，与从饮食中去除胆碱后出现器官功能障碍迹象的野生型42人相比，优势比(OR)为42(p=0.03)；具有G78T胆碱脱氢酶SNP的绝经前妇女发生胆碱缺乏症状的OR值为20(p=0.04)，具有共同亚甲基四氢叶酸脱氢酶(MTHFD1-1958A)SNP的绝经前妇女发生胆碱缺乏的OR值为&gt；85(p=0.0001)。我们发现胆碱脱氢酶A40中的另一个SNP与所有受试者对胆碱缺乏症状的易感性降低有关(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，我们的受试者中有18%是SNP纯合子，56%是杂合子，26%是野生型。因此，我们必须更好地了解这些基因多态是如何影响胆碱的饮食需求的。我们提出的研究将延长我们在上一个资助期的观察范围，并将完善我们对影响人类胆碱饮食需求的因素的理解。有人提议进行实验，以确定接受雌激素治疗的绝经后妇女是否有较低的胆碱需求，识别功能上重要的SNPs，确定这些SNPs在人群中的患病率，并检查使用这些SNPs的人类的饮食胆碱需求。

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.