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

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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.