Choline Polymorphisms in FASD

摘要 CIFASD的这一探索性/开发性UH2试点应用解决了改进干预的需求 在胎儿酒精谱系障碍(FASD)中，这是导致终身行为和认知障碍的主要原因。 这项提案的重点是营养胆碱，一种对大脑健康至关重要的单碳供体。 发展。胆碱代谢基因的多态影响胆碱的合成、运输和利用。 从而影响胆碱的需求和使用效果。强有力的临床前数据表明，胆碱补充- 无论是在宫内还是在出生后--减轻因产前酒精暴露(PAE)而造成的认知缺陷。临床 研究有更细微的结果，而胆碱补充剂带来的益处更少，甚至没有； 然而，年龄、大脑发育阶段和持续时间等变量混淆了这一解释。我们的 最近对沃兹尼亚克干预的受试者进行的SNP分析发现，胆碱的多态 转运蛋白SLC44A1(CTL1)预测谁从胆碱中受益最多；具体地说，受试者有未成年人 当给予补充胆碱时，SLC44A1的等位基因有最大的记忆改善。SLC44A1是 其活性因胆碱摄入量低而降低，这些次要等位基因进一步降低其活性。 因此，那些带有次要等位基因的人最容易受到胆碱缺乏的影响，并从其 补充。在这里，我们与CIFASD的研究人员合作，研究SLC44A1在FASD中的作用。 具体地说，我们假设SLC44A1基因的多态显著影响 FASD，在存在和不存在胆碱干预的情况下。目标1测试的假设是，在 乌克兰干预试验，SLC44A1等位基因较少的PAE孕妇认知能力最强 从补充胆碱中受益。Aim 2测试假设，在被诊断为FASD和 如果不服用胆碱，那些在SLC44A1中有少量等位基因的人的认知表现将最差。目标 3在人类神经元谱系中表达这些微小的等位蛋白，以了解其功能 这些变异对胆碱运输和新陈代谢的影响。AIMS 1-2利用CIFASD数据库，在 与CIFASD调查人员克里斯蒂娜·钱伯斯、塔蒂亚娜·福劳德和杰弗里·沃兹尼亚克以及 胆碱专家史蒂文·泽泽尔。这些发现(I)确定谁从胆碱干预中受益最多；(Ii)告知 胆碱如何改善FASD的预后；以及(Iii)使胆碱干预得以优化。本研究 代表了个性化医学在FASD中的第一次应用。这些结果使我们有资格加入CIFASD U01，将验证SLC44A1在妊娠药物滥用的独立队列中对S的影响， 检测进一步影响胆碱干预反应的其他胆碱相关多态。

ABSTRACT This exploratory/developmental UH2 pilot application to CIFASD addresses the need for improved intervention in Fetal Alcohol Spectrum Disorder (FASD), a leading cause of life-long behavioral and cognitive disability. This proposal focuses on the nutrient choline, a one-carbon donor that is essential for healthy brain development. Polymorphisms in choline-metabolizing genes affect its synthesis, transport, and utilization, and thus affect choline need and efficacy of its use. Strong preclinical data show that choline supplementation – both in utero and postnatally – mitigates the cognitive deficits due to prenatal alcohol exposure (PAE). Clinical studies have more nuanced outcomes, and choline supplements confer more modest or even no benefit; however, variables including age, developmental brain stage, and duration confound the interpretation. Our recent SNP analysis of subjects in the Wozniak intervention found that polymorphisms in the choline transporter SLC44A1 (CTL1) predict who benefited most from choline; specifically, subjects having minor alleles in SLC44A1 have the greatest memory improvement when given supplemental choline. SLC44A1 is ubiquitous and its activity is reduced by low choline intake, and these minor alleles further reduce its activity. Thus, those with the minor alleles are the most vulnerable to choline inadequacy and benefit most from its supplementation. Here, we collaborate with CIFASD investigators to investigate the role of SLC44A1 in FASD. Specifically, we hypothesize that polymorphisms in SLC44A1 significantly influence behavioral outcomes in FASD, in both the presence and absence of choline intervention. Aim 1 tests the hypothesis that, within the Ukrainian intervention trial, those PAE pregnancies with minor alleles in SLC44A1 derive the greatest cognitive benefit from choline supplementation. Aim 2 tests the hypothesis that, of individuals diagnosed with FASD and not receiving choline, those having minor alleles in SLC44A1 will have the poorest cognitive performance. Aim 3 expresses these minor allelic proteins in a human neuronal lineage, to understand the functional consequence of these variants to choline transport and metabolism. Aims 1-2 utilize the CIFASD database, in a collaboration with CIFASD investigators Christina Chambers, Tatiana Foroud and Jeffrey Wozniak, and with choline expert Steven Zeisel. These findings (i) identify who benefits most from choline intervention; (ii) informs how choline improves outcomes in FASD; and (iii) enables optimization of the choline intervention. This study represents the first application of Personalized Medicine to FASD. The results position us to join a CIFASD U01 that would validate SLC44A1's influence in an independent cohort of gestational substance abuse, with testing for additional choline-related polymorphisms that further influence response to choline intervention.