Mechanistic and metabolomic underpinnings of ALDH1L1 polymorphisms in the regulation of glycine metabolism

ALDH1L1 多态性调节甘氨酸代谢的机制和代谢组学基础

• 批准号: 10870688
• 负责人: SERGEY A KRUPENKO
• 金额: $ 24.57万
• 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: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10870688
• 关键词: Address; Affect; African; African American population; Alleles; Anabolism; Asian; Asian Americans; Carbon; Child; Collaborations; County; Diet; Disease; East Asian; Enzymes; Ethnic Origin; Ethnic Population; Etiology; Evaluation; Folic Acid; Folic Acid Deficiency; Formyltetrahydrofolates; Frequencies; Funding; Genes; Genetic Polymorphism; Genotype; Glycine; Grant; Haplotypes; Health; Health Alliance; High Prevalence; Hispanic; Hispanic Populations; Homeostasis; Human; Individual; Intake; Knock-out; Knowledge; Latin American; Left; Link; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic Pathway; Metabolic stress; Metabolism; Methylation; Minor; Mus; Nutrient; Obesity; Outcome; Oxidoreductase; Parents; Pathology; Pathway interactions; Patient Recruitments; Patients; Play; Population; Predisposition; Pregnancy Complications; Pregnant Women; Prevalence; Property; Purines; Regulation; Reporting; Research; Risk Factors; Role; Serine; Serum; Single Nucleotide Polymorphism; Source; South African; South Asian; Underrepresented Populations; Underserved Population; Variant; Vitamins; aldehyde dehydrogenases; caucasian American; cohort; design; dietary; disorder risk; folic acid metabolism; metabolic phenotype; metabolome; metabolomics; novel; parent grant; prevent; recruit; response; response biomarker; southeast Asian; vitamin metabolism

SUMMARY This request for a supplement to R01126666 is for funds to assemble a novel cohort of pregnant women residing in Cabarrus County, NC which will be added through a collaboration with the Cabarrus Health Alliance (CHA). Recruited participants of this study will be assessed for non-synonymous SNPs in the major folate enzyme ALDH1L1. These SNPs will be linked to serum metabolome and analyzed as potential markers of metabolic health and pregnancy complications. ALDH1L1, a common folate enzyme, regulates major metabolic pathways including the de novo purine biosynthesis and folate-linked methylation, and plays a key role in controlling the flux of one-carbon groups to anabolic pathways. In support of this key role, the knockout of the ALDH1L1 gene in mice causes functional folate deficiency and dysregulate glycine metabolism. We have further reported that human ALDH1L1 has six common non-synonymous exonic SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717 and rs4646750 with the occurrence of haplotypes associated with these SNPs being remarkably different between ethnic populations. Our analysis of an established cohort of Hispanic children, Viva La Familia, has shown a significant reduction of serum glycine and increase in serine/glycine ratio in children with rs2276724 and rs3796191, indicating deregulation of serine to glycine conversion and re- capitulating our mouse findings. ALDH1L1 non-synonymous SNPs were also associated with markers of metabolic stress and adiposity in this cohort. Based on our findings, we hypothesized in the parental grant that individuals with non-synonymous ALDH1L1 SNPs have dysregulated glycine metabolism which affects metabolic health, the outcome especially critical for pregnant women. The preliminary analysis of NACS pregnant women cohort has shown that this cohort recruits primarily Caucasians and African-Americans, which limits the analysis of certain ALDH1L1 haplotypes. To overcome this matter and include more underrepresented and underserved populations, we plan to add the predominantly Hispanic CHA cohort. Aim 1 Supplement (the extension of Aim 3 of the parental grant). Link ALDH1L1 haplotypes to the folate-dependent regulation of glycine metabolism in humans in the CHA cohort. 1.1. Assemble and genotype a novel cohort of pregnant women based on the Cabarrus Health Alliance (CHA) patients. 1.2. Determine the serum metabotype for major ALDH1L1 haplotypes in these cohorts using targeted and untargeted metabolomics. 1.3. Establish the associations among ALDH1L1 SNPs, glycine metabolism, folate status and health outcomes in the CHA cohort. ALDH1L1 variants are very common in different populations but their role in folate homeostasis and in the etiology of metabolic disease is largely unexplored. It is expected that ALDH1L1 haplotypes differently mediate the metabolic response to dietary folate that might require adjustments of folate intake for individuals bearing certain ALDH1L1 SNPs. By filling this knowledge gap, the proposed research will lay ground for the evaluation of population-specific ALDH1L1 haplotypes as a disease risk factor.

概括 对 R01126666 的补充申请是为了筹集资金来组建一批新的居住孕妇 位于北卡罗来纳州卡巴勒斯县，该项目将通过与卡巴勒斯健康联盟 (CHA) 合作添加。 本研究招募的参与者将接受主要叶酸酶中非同义 SNP 的评估 ALDH1L1。这些 SNP 将与血清代谢组相关联，并作为潜在的代谢标志物进行分析 健康和妊娠并发症。 ALDH1L1 是一种常见的叶酸酶，调节主要代谢途径 包括从头嘌呤生物合成和叶酸相关甲基化，并在控制 一碳基团向合成代谢途径的通量。为了支持这一关键作用，ALDH1L1 基因的敲除 小鼠体内会导致功能性叶酸缺乏和甘氨酸代谢失调。我们还进一步报道称 人类 ALDH1L1 在多态性位点 rs3796191、rs2886059、 rs9282691、rs2276724、rs1127717 和 rs4646750 以及与这些相关的单倍型的出现 SNP 在种族人群之间存在显着差异。我们对西班牙裔人群的分析 儿童 Viva La Familia 已显示出血清甘氨酸显着降低和丝氨酸/甘氨酸比率增加 在具有 rs2276724 和 rs3796191 的儿童中，表明丝氨酸向甘氨酸转化的失调和重新调节 放弃我们的小鼠发现。 ALDH1L1 非同义 SNP 也与以下标记相关： 该队列中的代谢应激和肥胖。根据我们的发现，我们在父母补助金中假设： 具有非同义 ALDH1L1 SNP 的个体甘氨酸代谢失调，从而影响 代谢健康，其结果对于孕妇尤其重要。 NACS妊娠的初步分析 女性队列表明，该队列主要招募白人和非裔美国人，这限制了 某些 ALDH1L1 单倍型的分析。为了解决这个问题并让更多的代表性不足和 针对服务不足的人群，我们计划增加以西班牙裔为主的 CHA 群体。目标 1 补充（ 延长父母补助金的目标 3）。将 ALDH1L1 单倍型与叶酸依赖性调节联系起来 CHA 队列中人类的甘氨酸代谢。 1.1.组装新的孕妇群体并进行基因分型 基于卡巴鲁斯健康联盟 (CHA) 患者的女性。 1.2.确定主要的血清代谢型 使用靶向和非靶向代谢组学分析这些队列中的 ALDH1L1 单倍型。 1.3.建立 CHA 队列中 ALDH1L1 SNP、甘氨酸代谢、叶酸状态和健康结果之间的关联。 ALDH1L1 变异在不同人群中非常常见，但它们在叶酸稳态和叶酸稳态中的作用 代谢性疾病的病因在很大程度上尚未被探索。预计 ALDH1L1 单倍型以不同方式介导 对膳食叶酸的代谢反应可能需要调整生育个体的叶酸摄入量 某些 ALDH1L1 SNP。通过填补这一知识空白，拟议的研究将为评估奠定基础 人群特异性 ALDH1L1 单倍型作为疾病危险因素。

项目成果

Exploratory Metabolomics Underscores the Folate Enzyme ALDH1L1 as a Regulator of Glycine and Methylation Reactions.

• DOI: 10.3390/molecules27238394
• 发表时间: 2022-12-01
• 期刊: Molecules (Basel, Switzerland)
• 作者: Rushing BR;Fogle HM;Sharma J;You M;McCormac JP;Molina S;Sumner S;Krupenko NI;Krupenko SA
• 通讯作者: Krupenko SA

Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice.

• DOI: 10.3390/metabo12050454
• 发表时间: 2022-05-18
• 期刊: Metabolites
• 影响因子: 4.1