A Metabolome Wide Association Study of Fruit and Vegetable Consumption and Associations with Cardiovascular Disease Risk Factors: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) Study

Abstract

Background: Epidemiologic evidence linking blood pressure (BP) and body weight-lowering effects with fruit and vegetable consumption mostly relies on self-reported dietary assessment prone to misreport and under- or overestimation of relationships. Objectives: We aimed to characterize objective 24-h urinary metabolites and a derived metabolite score associated with fruit and vegetable intake and assessed their associations with BP and BMI, with validation across cohorts. Methods: We used untargeted proton nuclear magnetic resonance spectroscopy (1H NMR) of 2 timed repeated 24-h urine collections from free-living participants from the US (n = 2032) and the UK (n = 449) of the cross-sectional International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). We evaluated correlations between fruit and vegetable intake assessed by 24-h dietary recalls with 7100 1H NMR features, adjusted for confounders and multiple testing. We related identified metabolites and a metabolite score with BP and BMI using extensively adjusted multiple linear regression models. Results: We characterized 11 1H NMR-derived 24-h urinary metabolites related to fruit and vegetable intake, reproducible across multiple 24-h urine collections of both cohorts. Proline betaine, citrate, N-methylproline, scyllo-inositol, 2-hydroxy-2-(4-methyl cyclohex-3-en-1-yl) propoxyglucuronide, and proline were associated with fruit intake, specifically with Rutaceae intake, whereas S-methyl-L-cysteine sulfoxide and S-methyl-L-cysteine sulfoxide metabolite were associated with Brassicaceae intake. The metabolite score, explaining 39.8% of fruit and vegetable intake, was inversely associated with systolic BP [−1.65 mmHg; 95% confidence interval (CI): −2.68, −0.62; P < 0.002] and BMI (−1.21 kg/m2; 95% CI: −1.62, −0.78; P < 0.0001). These associations were, to a large extent, explained by urinary citrate excretion. Conclusions: We identified 1H NMR-derived urinary metabolites associated with fruit and vegetable consumption, consistent and reproducible between urine collections and across populations. A higher fruit and vegetable-related metabolite score showed associations with lower systolic BP and BMI, mainly mediated by citrate, but would need confirmation in further studies.