Abstract
BACKGROUND: Little is known about the associations between choline metabolites (total choline, phosphatidylcholine, and glycine) and the incidence of heart failure (HF). OBJECTIVES: The purpose of this study was to assess the associations of choline metabolites with incident HF and examine the effect modification by genetic susceptibility. METHODS: This prospective cohort study followed 245,072 participants from the UK Biobank from baseline (2006-2010) until March 30, 2023. Participants were free of cardiovascular diseases at baseline. Circulating choline metabolites were quantitated using nuclear magnetic resonance spectrometer. Cox proportional hazards models were fitted to assess the association of choline metabolites and genetics with incident HF. Two-sample Mendelian randomization analyses were implemented to confirm the findings in observational analysis. RESULTS: During a median follow-up of 14.1 years, 5,468 incident HF cases were documented. Total choline and phosphatidylcholine were positively associated with HF risk (HR: 1.08 [95% CI: 1.04-1.12] and HR: 1.08 [95% CI: 1.05-1.12], per one SD increase, respectively). Compared with the lowest quartile group, the HR for the highest quartile group was 1.23 (95% CI: 1.12-1.35) for total choline and 1.23 (95% CI: 1.12-1.34) for phosphatidylcholine. Glycine was inversely associated with HF risk (HR: 0.97 [95% CI: 0.94-0.99], per one SD increase). Participants with high polygenic risk score and high total choline or phosphatidylcholine had the highest risk of HF, whereas participants with low polygenic risk score and high glycine had the lowest risk. No statistically significant interactions were observed between choline metabolites and genetic susceptibility to HF. The Mendelian randomization analysis supported the potential causal associations of total choline (OR: 1.71 [95% CI: 1.01-1.35]) and glycine (OR: 0.93 [95% CI: 0.88-0.99]) with HF. CONCLUSIONS: Circulating choline metabolites were associated with the risk of incident HF, independent of genetic susceptibility. Whether targeting the metabolic pathway of choline might be a potential strategy for improving heart health warrants further validation.