Circulating metabolites may illustrate relationship of alcohol consumption with cardiovascular disease

Abstract

Background: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.

Methods: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure).

Results: We identified 60 metabolites associated with cumulative average alcohol consumption (p < 0.05/211 ≈ 0.00024). For example, 1 g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta = 0.023 ± 0.002, p = 6.3e - 45) and phosphatidylcholine (e.g., PC 32:1, beta = 0.021 ± 0.002, p = 3.1e - 38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11 (95% CI = [1.02, 1.21], p = 0.02) vs 0.88 (95% CI = [0.78, 0.98], p = 0.02).

Conclusions: We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.

Keywords: Alcohol consumption; Cardiovascular disease; Metabolites.

Fig. 1

The study flowchart

Fig. 2

Volcano plot for association of cumulative average alcohol consumption and metabolites. Linear mixed model was performed adjusting for age, sex, batch, smoking status, BMI, physical activity index, and diet score as fixed effect, and family relationship as random effect. Blue dots represent significant relationship (p value < 0.00024), grey dots represent non-significant relationship. CE cholesteryl ester, PC phosphatidylcholine, TAG triacylglycerol

Fig. 3

Comparison of association between different types of alcohol beverages. A Comparison of effect sizes between different types of alcohol beverages. B Comparison of -log 10 (p values) between different types of alcohol beverages. All linear mixed models adjusted for age, sex, batch, smoking status, BMI, physical activity index and diet score as fixed effect, and family relationship as random effect. CE cholesterol esters, DAG diacylglycerols, LPC lysophosphatidylcholines, LPE lysophosphatidylethanolamines, PC phosphatidylcholines, SM sphingomyelins, TAG triacylglycerols. Metabolites shown in panel had significant association with at least one type of alcohol (beer, wine, and liquor) or total alcohol consumption

Fig. 4

Comparison of associations of cumulative average alcohol consumption and metabolites between men and women. Linear mixed model was performed in women-only and men-only samples. Covariates included age, batch, smoking status, BMI, physical activity index and diet score as fixed effect, and family relationship as random effect. CE cholesteryl ester, PC phosphatidylcholine, TAG triacylglycerol

Fig. 5

Forest plot for CVD with metabolite composite score. Seven-met, the weighted score obtained from seven metabolites, TAG 50:2, TAG 50:1, TAG 48:1, TAG 48:0, TAG 46:0, PC 32:1, and glutamine; three-met, the weighted score obtained from three metabolites, TAG 52:3, isoleucine, and leucine. Weights were obtained from the beta coefficients of association test between cumulative average alcohol consumption and metabolites in linear mixed models. In the Cox regression, base model included age, sex, and batch as covariates, and multivariable model additionally adjusted for BMI, SBP, hypertension treatment status, diabetes, smoking status, and total and high-density lipoprotein cholesterol level