Abstract
Single nucleotide polymorphisms (SNPs) in choline metabolizing genes are associated with disease risk and greater susceptibility to organ dysfunction under conditions of dietary choline restriction. However, the underlying metabolic signatures of these variants are not well characterized and it is unknown whether genotypic differences persist at recommended choline intakes. Thus, we sought to determine if common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting and exceeding current recommendations. Women (n = 75) consumed 480 or 930 mg choline/day (22% as a metabolic tracer, choline-d9) for 10–12 weeks in a controlled feeding study. Genotyping was performed for eight variant SNPs and genetic differences in metabolic flux and partitioning of plasma choline metabolites were evaluated using stable isotope methodology. CHKA rs10791957, CHDH rs9001, CHDH rs12676, PEMT rs4646343, PEMT rs7946, FMO3 rs2266782, SLC44A1 rs7873937, and SLC44A1 rs3199966 altered the use of choline as a methyl donor; CHDH rs9001 and BHMT rs3733890 altered the partitioning of dietary choline between betaine and phosphatidylcholine synthesis via the cytidine diphosphate (CDP)-choline pathway; and CHKA rs10791957, CHDH rs12676, PEMT rs4646343, PEMT rs7946 and SLC44A1 rs7873937 altered the distribution of dietary choline between the CDP-choline and phosphatidylethanolamine N-methyltransferase (PEMT) denovo pathway. Such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term.
Highlights
Choline is an essential micronutrient with critical roles in a wide-array of physiologic processes [1].As a source of methyl groups, choline supports cellular methylation reactions, including genomic methylation, which influences gene expression and DNA stability
Figure of of thethe rs3199966 variant on the flux and partitioning of dietary rs3199966 variant onmetabolic the metabolic flux and partitioning of choline. These results demonstrate that common genetic variants in choline metabolizing genes alter the. These results demonstrate that common genetic variants in choline metabolizing genes alter metabolic signature of choline in three ways: (i) the use of dietary choline as a methyl donor
Our results suggest that women with the rs9001 variant partition dietary choline to the cytidine diphosphate (CDP)-choline pathway at the expense of betaine synthesis
Summary
Choline is an essential micronutrient with critical roles in a wide-array of physiologic processes [1]. As a source of methyl groups, choline supports cellular methylation reactions, including genomic methylation, which influences gene expression and DNA stability. Choline serves as the substrate for the formation of acetylcholine, a neurotransmitter and non-neuronal cell-signaling molecule. The primary metabolic fate of choline is biosynthesis of phosphatidylcholine (PC), the most abundant phospholipid in cell membranes [2].
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