Choline Polymorphisms in FASD

FASD 中的胆碱多态性

• 批准号: 10331893
• 负责人: SUSAN M. SMITH
• 金额: $ 17.49万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331893
• 关键词: 3' Untranslated Regions; Address; Affect; Age; Alleles; Behavioral; Biochemical; Brain; Carbon; Cell Line; Cell membrane; Child; Choline; Clinical Research; Clinical Trials; Code; Cognition; Cognitive; Cognitive deficits; Collaborations; Data; Databases; Development; Diagnosis; Dose; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Future; GTP-Binding Protein alpha Subunits, Gs; Genes; Genetic; Genetic Polymorphism; Genotype; Human; Individual; Infant; Intake; Intervention; Intervention Trial; Investigation; Life; Link; Memory; Metabolism; Minor; Modeling; Neurons; Nutrient; Outcome; Phase; Pilot Projects; Positioning Attribute; Pregnancy; Prevention; Protein Isoforms; Proteins; Reporting; Research Personnel; Role; Shapes; Single Nucleotide Polymorphism; Source; Substance abuse problem; Supplementation; Testing; Toddler; Variant; Woman; Work; behavior influence; behavioral outcome; choline supplementation; choline transporter; cognitive benefits; cognitive disability; cognitive performance; cohort; dietary; disability; experience; genetic variant; improved; improved outcome; in utero; molecular sequence database; neurobehavior; neurobehavioral; novel; nutrition; personalized medicine; postnatal; pre-clinical; prenatal; response; success; whole genome

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.

抽象的 CIFASD 的这一探索性/发展性 UH2 试点应用解决了改进干预的需要 胎儿酒精谱系障碍 (FASD)，这是导致终生行为和认知障碍的主要原因。 该提案重点关注营养胆碱，这是一种对健康大脑至关重要的单碳供体 发展。胆碱代谢基因的多态性影响其合成、运输和利用，并且 从而影响胆碱的需求及其使用的功效。强有力的临床前数据表明，补充胆碱 – 在子宫内和产后 – 减轻由于产前酒精暴露 (PAE) 造成的认知缺陷。临床 研究结果更加微妙，而胆碱补充剂带来的益处更有限，甚至没有益处； 然而，年龄、大脑发育阶段和持续时间等变量使解释变得混乱。我们的 最近对沃兹尼亚克干预中的受试者进行的 SNP 分析发现，胆碱中的多态性 转运蛋白 SLC44A1 (CTL1) 预测谁从胆碱中获益最多；具体来说，科目有轻微 当补充胆碱时，SLC44A1 中的等位基因具有最大的记忆改善效果。 SLC44A1是 无处不在，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，具有次要等位基因的人最容易受到胆碱不足的影响，并从胆碱中受益最多。 补充。在这里，我们与 CIFASD 研究人员合作研究 SLC44A1 在 FASD 中的作用。 具体来说，我们假设 SLC44A1 的多态性显着影响行为结果 FASD，无论是否存在胆碱干预。目标 1 检验以下假设： 乌克兰干预试验显示，SLC44A1 中具有较小等位基因的 PAE 妊娠获得了最大的认知能力 受益于胆碱补充。目标 2 检验以下假设：被诊断患有 FASD 的个体和 如果不接受胆碱，那些在 SLC44A1 中具有次要等位基因的人的认知能力将最差。目的 3 在人类神经元谱系中表达这些次要等位蛋白，以了解其功能 这些变异对胆碱运输和代谢的影响。目标 1-2 利用 CIFASD 数据库， 与 CIFASD 调查员 Christina Chambers、Tatiana Foroud 和 Jeffrey Wozniak 合作，并与 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大； (二) 通知 胆碱如何改善 FASD 的预后； (iii) 能够优化胆碱干预。这项研究 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 U01 将验证 SLC44A1 在妊娠期药物滥用的独立队列中的影响， 测试其他与胆碱相关的多态性，这些多态性进一步影响对胆碱干预的反应。