Common genetic polymorphisms define one-carbon metabolite response to different forms of choline in healthy adult males

Nisa Butt¹Jianzhang Dong¹Gia V Shelp¹Elizabeth M Poole²Justine R Keathley¹Bakovic Marica¹Clara E Cho^1*

• ¹Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada
• ²Department of Family Relations and Applied Nutrition, University of Guelph, Guelph, Canada

Background: Responsiveness to nutrients can be determined by many types of variations including single nucleotide polymorphisms (SNPs). Choline is an essential nutrient critical for proper organ function and exists in different forms such as free choline or as derivatives including phosphatidylcholine (PC). Although genetic variations in genes encoding enzymes that influence choline metabolism have been identified, little is known regarding individual responses to free choline and PC in relation to SNPs. Here, we determined the effect of different forms of choline, genotype and their interaction on one-carbon metabolite concentrations in urine, which has utility in capturing the overall change in choline metabolism. Methods: A randomized, double-blinded, crossover study was conducted in healthy adult males (n=37) who were provided with a standardized meal containing 600 mg choline either as choline bitartrate (CB) or PC, or no choline (NC) control. Urine was collected at study baseline and pooled throughout the 6-h study duration. Choline dehydrogenase (CHDH) rs12676, betaine-homocysteine S-methyltransferase (BHMT) rs3733890, choline kinase alpha (CHKA) rs10791957 and phosphatidylethanolamine N-methyltransferase (PEMT) rs4646343 were genotyped. Results: There was a main treatment effect for urinary choline change from baseline reflective of differences in absorption by free choline versus PC (p<0.01). A reduction in responsiveness to CB was found with genetic variations in CHDH rs12676 manifested as lower choline oxidation (p<0.05) and downstream pathways in the methionine cycle (p<0.01) whereas a reduction in responsiveness to PC occurred with genetic variations in BHMT rs3733890 (p<0.05). Genetic variations in CHKA rs10791957 and PEMT rs4646343 reflected differences in the partitioning of choline in response to CB and PC (p<0.01). Multivariate analysis showed that groups with accumulated number of effect This is a provisional file, not the final typeset article alleles across all SNPs have contrasting responses to CB and PC that deviate from the patterns derived from treatment effect alone (p<0.05). Conclusion:Unique metabolite signatures in one-carbon metabolism arise in response to supplemental intake of different forms of choline driven by genetic variations that regulate choline homeostasis. Our findings highlight the importance of nutrient-gene interactions in deciphering the complexity of individual metabolic responses supporting the emerging concept of precision nutrition.