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

总结 R 01126666的补充申请是为了获得资金，以收集一个新的孕妇队列， 在卡巴鲁斯县，北卡罗来纳州，这将通过与卡巴鲁斯健康联盟（CHA）的合作增加。 本研究招募的参与者将评估主要叶酸酶中的非同义SNP ALDH1L1。这些SNPs将与血清代谢组相关联，并作为代谢的潜在标志物进行分析。 健康和妊娠并发症。ALDH 1 L1是一种常见的叶酸酶，调节主要的代谢途径 包括从头嘌呤生物合成和叶酸连接的甲基化，并在控制 一碳基团向合成代谢途径的流动。为了支持这一关键作用，ALDH 1 L1基因的敲除 导致功能性叶酸缺乏和甘氨酸代谢失调。我们进一步报道， 人ALDH 1 L1在多态性基因座rs3796191，rs 2886059， rs 9282691、rs 2276724、rs 1127717和rs 4646750与这些相关的单倍型的发生有关 SNPs在不同种族人群之间存在显著差异。我们分析了一组西班牙裔 儿童，Viva La Familia，显示血清甘氨酸显著降低，丝氨酸/甘氨酸比率增加 在rs 2276724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。 我们的老鼠研究成果ALDH 1 L1非同义SNPs也与ALDH 1 L1的标记物相关。 代谢应激和肥胖的关系根据我们的发现，我们在父母补助金中假设， 具有非同义ALDH 1 L1 SNP的个体具有失调的甘氨酸代谢， 代谢健康，结果对孕妇尤其重要。NACS妊娠的初步分析 女性队列表明，这一队列主要招募高加索人和非洲裔美国人，这限制了 ALDH 1 L1单倍型分析。为了解决这一问题， 我们计划增加以西班牙裔为主的CHA队列。目标1补编（ （扩大父母补助金的目标3）。ALDH 1 L1单倍型与叶酸依赖性调节 CHA队列中人体的甘氨酸代谢。1.1.组装和基因分型一个新的队列怀孕 卡巴鲁斯健康联盟（CHA）的患者。1.2.测定血清代谢型主要 ALDH 1 L1单倍型在这些队列中使用靶向和非靶向代谢组学。1.3.建立 CHA队列中ALDH 1 L1 SNPs、甘氨酸代谢、叶酸状态和健康结果之间的相关性。 ALDH 1 L1变异体在不同人群中非常常见，但它们在叶酸稳态中的作用和在 代谢性疾病的病因学在很大程度上还未被探索。预计ALDH 1 L1单倍型不同地介导了 对膳食叶酸的代谢反应，可能需要调整叶酸摄入量， ALDH1L1 SNPs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ALDH 1 L1单倍型作为疾病风险因素。

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.