Genetic Variation in Choline‐Metabolizing Enzymes Alters Choline Dynamics in Women Meeting Current Dietary Recommendations

Abstract

Choline Kinase-α (CHKA) rs10791957, choline dehydrogenase (CHDH) rs9001, and CHDH rs12676 are genetic risk factors for disease and choline deficiency. While these single nucleotide polymorphisms are known to alter disease risk and the minimum choline intake needed for prevention of acute muscle and liver pathologies, their underlying metabolic signatures are not well characterized and it is unknown whether metabolic differences persist under conditions of nutrient adequacy. We sought to determine if these genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting current recommendations. Women consumed 480 or 930 mg choline/d (22% as choline-d9, a metabolic tracer) for 10–12 weeks in a controlled feeding study and stable isotope methodology was used to investigate the effect of genetic differences on choline dynamics. CHKA rs10791957 (Figure 1), CHDH rs9001 (Figure 2), and CHDH rs12676 (Figure 3) all influenced choline dynamics under the study conditions of nutrient adequacy. Variants associated with decreased risk for choline deficiency (CHKA rs10791957, CHDH rs9001) appeared to favor cytidine diphosphate (CDP)-phosphatidylcholine (PC) synthesis relative to phosphatidylethanolamine N-methyltransferase (PEMT)-PC synthesis as compared to non-variants, while the CHDH rs12676 genotype, which is associated with increased risk, favored PEMT-PC synthesis. These results are consistent with the effect of these variants on choline requirements when one considers efficiency of PC production. While each unit of choline directed to the CDP-choline pathway yields one unit of PC, choline converted to betaine (and eventually S-adenosylmethionine) has many metabolic fates besides PEMT-PC production, and three choline-derived methyl groups are needed to yield just one additional unit of PC via the PEMT pathway. Therefore, greater PEMT-PC production may constitute a drain on choline status and exacerbate disease risk during choline deficiency. Our results indicate that these SNPs have metabolic effects at choline intakes relevant to the general population and such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term. In fact, decreased PEMT activity observed among CHKA rs10791957 variant women (decreased turnover of choline-derived methionine → PEMT-PC; p=0.0005) may provide a metabolic basis for the decreased risk of type 2 diabetes among CHKA rs10791957 variant individuals given that PEMT knockout mice are protected from high-fat diet induced obesity and insulin resistance. Overall, these findings highlight the need for further study to examine the effects of genetic differences in choline metabolism on chronic disease outcomes. Support or Funding InformationThis work was supported by the National Institutes of Health under award T32-DK007158 and by the USDA National Institute of Food and Agriculture, Hatch project 231646. The content is the responsibility of the authors and does not necessarily represent the views of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institutes of Health or the National Institute of Food and Agriculture (NIFA) or the United States Department of Agriculture(USDA). Figure 1Open in figure viewerPowerPoint Effect of the CHKA rs10791957 variant on the metabolite flux and partitioning of dietary choline Figure 2Open in figure viewerPowerPoint Effect of the CHDH rs9001 variant on the metabolite flux and partitioning of dietary choline. Figure 3Open in figure viewerPowerPoint Effect of the CHDH rs12676 variant on the metabolite flux and partitioning of dietary choline.