Choline and its metabolites are differentially associated with cardiometabolic risk and cardio‐ and cerebro‐vascular disease

Abstract

Considerable attention has recently been given to the potential role of choline in cardiovascular disease. While the main focus has been on the microbial metabolism of phosphatidylcholine and the production of a pro‐atherosclerotic metabolite trimethylamine‐N‐oxide, there are also a number of links between choline and cardiometabolic risk through its role in lipid and one‐carbon metabolism. Phosphatidylcholine, a metabolite of choline, is an essential component of lipoproteins, and its biosynthesis in the liver is critical for the synthesis and secretion of very‐low density lipoproteins. Choline is also a precursor of betaine, which is a methyl donor for the conversion of homocysteine (Hcy) to methionine. Some data suggest differing associations of plasma choline and betaine with components of the metabolic syndrome, with an unfavorable cardiovascular risk profile associated with higher choline and a more favorable one with higher betaine plasma concentrations. Whether this same relationship holds true for cerebrovascular disease has not yet been evaluated. In this study, we've evaluated the associations of plasma choline and choline‐related compounds with cardiometabolic risk factors, history of cardiovascular disease, and cerebrovascular pathology in a cross‐sectional analysis of 293 men and women (mean age = 75 years, sd = 8.6) from the Nutrition, Aging, and Memory in Elders (NAME) cohort who had undergone magnetic resonance imaging of the brain and anthropometric and blood pressure measurement, had archived fasting plasma, and who had been administered a health history questionnaire. Plasma concentrations of choline, phophatidylcholine, and betaine were measured using liquid chromatography‐stable isotope dilution‐multiple reaction monitoring –mass spectrometry. Multiple linear and logistic regression models were used to examine relationships of plasma measures with cardiometabolic risk factors, history of cardiovascular disease, and radiological evidence of cerebral large vessel and small vessel infarcts. We found that plasma concentrations of phosphatidylcholine were positively related to low‐density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglycerides (TG) (p<0.0001 for all), while the ratio of plasma betaine to choline concentrations were positively related to HDL (p=0.02) and negatively related to TG and Hcy (p<0.0001 for both). Higher concentrations of both metabolites were associated with lower risk of hypertension (3rd vs 1st tertile, OR=0.42, 95% CI 0.18 – 0.99 for both). Participants in the third tertile of plasma choline concentrations had higher odds of having a history of cardiovascular disease (OR =3.26, 95% CI 1.67 – 6.36) and cerebral large vessel infarct (OR=4.19, 95% CI 1.2 – 13.58), but lower odds of cerebral small vessel infarct (OR=0.48, 95% CI 0.23 – 0.98). Our findings that choline and its metabolites had differential associations with cardiometabolic risk factors and subtypes of vascular disease suggest differing roles in the pathogenesis of cardiovascular and cerebral large vessel disease versus small vessel disease.Support or Funding InformationUSDA agreement No. 58‐1950‐0‐014; NIA AG21790‐01; NHLBIT32‐HL069772