Choline Polymorphisms in FASD

摘要 UH 2在CIFASD中的探索性/开发性试点应用解决了改善干预的需求 胎儿酒精谱系障碍（FASD），终身行为和认知障碍的主要原因。 这项建议的重点是营养胆碱，一个碳供体，是必不可少的健康的大脑 发展胆碱代谢基因的多态性影响其合成、转运和利用， 从而影响胆碱的需要及其使用功效。强有力的临床前数据表明，胆碱补充剂- 无论是在子宫内和产后-减轻认知缺陷，由于产前酒精暴露（PAE）。临床 研究的结果更加微妙，胆碱补充剂带来的益处更小，甚至没有益处; 然而，包括年龄、大脑发育阶段和持续时间在内的变量混淆了解释。我们 最近对沃兹尼亚克干预的受试者进行的SNP分析发现， 转运蛋白SLC 44 A1（CTL 1）预测谁从胆碱中获益最多;特别是， SLC 44 A1中的等位基因在给予补充胆碱时具有最大的记忆改善。SLC 44 A1是 普遍存在，并且其活性因低胆碱摄入而降低，并且这些次要等位基因进一步降低其活性。 因此，那些具有次要等位基因的人最容易受到胆碱不足的影响，并从其受益最多。 补充。在这里，我们与CIFASD研究人员合作，调查SLC 44 A1在FASD中的作用。 具体地说，我们假设SLC 44 A1的多态性显著影响行为结果， FASD，在存在和不存在胆碱干预的情况下。目标1检验假设，在 乌克兰干预试验，那些在SLC 44 A1中具有次要等位基因的PAE妊娠获得了最大的认知能力， 补充胆碱的好处目的2测试的假设，即个人诊断为FASD和 不接受胆碱，那些在SLC 44 A1中具有次要等位基因的人将具有最差的认知表现。目的 3在人类神经元谱系中表达这些次要等位基因蛋白，以了解其功能。 这些变异对胆碱转运和代谢的影响。目标1-2利用CIFASD数据库， 与CIFASD调查员Christina Chambers，Tatiana Foroud和Jeffrey Wozniak合作， 胆碱专家史蒂文·蔡塞尔。这些发现（i）确定谁从胆碱干预中受益最多;（ii）通知 胆碱如何改善FASD的结果;（iii）能够优化胆碱干预。本研究 代表了个性化医疗在FASD中的首次应用。结果使我们能够加入CIFASD U 01，这将验证SLC 44 A1在妊娠期物质滥用的独立队列中的影响， 测试进一步影响对胆碱干预反应的其他胆碱相关多态性。

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.