Association of circulating metabolites with healthy diet and risk of cardiovascular disease: analysis of two cohort studies

Abstract

Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations - the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 ± 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 ± 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.

Figure 1

Age-, sex- and energy intake-adjusted associations between AHEI z-score and metabolites in Whitehall II study. Results are expressed as regression coefficients accompanied with their 95% confidence interval for one standard deviation increment in AHEI diet score. To facilitate comparison, metabolites were square root transformed and standardized to z-scores (mean = 0, SD = 1). P ≥ 0.0006; P < 0.0006.

Figure 2

Multivariable-adjusted associations between AHEI z-score and metabolites from meta-analysis of the Whitehall II Study and the Young Finns Study (YFS). Whitehall II study; YFS; Meta-analysis. Linear regression models were adjusted for age, sex, total energy intake, ethnicity, smoking habits, physical activity, type 2 diabetes, diastolic and systolic blood pressure, use of antihypertensive drugs and use of lipid-lowering drugs. Results are expressed as linear regression coefficients accompanied with their 95% confidence interval. To facilitate comparison, metabolites were first square root transformed and then standardized to z-scores (mean = 0, SD = 1).

Figure 3

Comparison of diet-metabolites associations and metabolites-incident CVD risk associations in Whitehall II study. Associations directionally concordant. Associations directionally discordant. On the left hand size: Linear regression models estimating the associations between AHEI z-score and the 41 selected metabolites performed in 4824 participants and adjusted for age, sex, total energy intake, ethnicity, smoking habits, physical activity, type 2 diabetes, diastolic and systolic blood pressure, use of antihypertensive drugs and use of lipid-lowering drugs. Results are expressed as linear regression coefficients accompanied with their 95% confidence interval. To facilitate comparison, metabolites were first square root transformed and then standardized to z-scores (mean = 0, SD = 1). On the right hand size: Cox proportional hazards regression models estimating the association between the selected 41 metabolites and the risk of incident CVD over the 15.8 years of follow-up, performed in 5840 Whitehall II participant, adjusted for age, sex, total energy intake, ethnicity, smoking habits, physical activity, type 2 diabetes, diastolic and systolic blood pressure, use of antihypertensive medication. Results are expressed as Hazard Ratio accompanied with their 95% confidence interval. To facilitate comparison, metabolites were first square root transformed and then standardized to z-scores (mean = 0, SD = 1).

Figure 4

Metabolomic profiles associated with low adherence to healthy dietary guidelines and with the risk of incident cardiovascular diseases -. The metabolic profiling analyses identified 41 metabolites associated with the adherence to healthy diet in Whitehall II study. Replication analyses in the Young Finns Study showed that most of these diet-metabolites associations were directionally concordant. We then assessed the extent to which each of the 41 metabolites associated with diet score also predicted CVD events over the 15.8 years of Whitehall II Study follow-up. Results showed that most of metabolites associated with poor adherence to healthy dietary guidelines are also related to higher CVD risk and consisted of amino acids, glycoprotein acetyls, size of lipoprotein particule size, lipids in lipoproteins, cholesterol and triglycerides and fatty acids. These findings highlight a specific fatty acid patterns robustly associated with both adherence to healthy diet and reduced risk of CVD. These specific fatty acids pattern consisted of lower levels of saturated and monounsaturated fatty acids and higher ratio of polyunsaturated fatty acids, omega-3 and docosahexaenoic acid relative to total fatty acids concentrations, possibly representing a molecular link between healthy diet and lower cardiovascular disease risk.

Figure 5

Flow chart diagram mapping the inclusion of Whitehall II and Young Finns Study participants.