Changes in Circulating Metabolome Precede Alcohol‐Related Diseases in Middle‐Aged Men: A Prospective Population‐Based Study With a 30‐Year Follow‐Up

BACKGROUND: Heavy alcohol use has been associated with altered circulating metabolome. We investigated whether changes in the circulating metabolome precede incident diagnoses of alcohol-related diseases. METHODS: This is a prospective population-based cohort study where the participants were 42- to 60-year-old males at baseline (years 1984 to 1989). Subjects who received a diagnosis for an alcohol-related disease during the follow-up were defined as cases (n = 92, mean follow-up of 13.6 years before diagnosis). Diagnoses were obtained through linkage with national health registries. We used 2 control groups: controls who self-reported similar levels of alcohol use as compared to cases at baseline (alcohol-controls, n = 92), and controls who self-reported only light drinking at baseline (control-controls, n = 90). A nontargeted metabolomics analysis of baseline serum samples was performed. RESULTS: There were significant differences between the study groups in the baseline serum levels of 64 metabolites: in amino acids (e.g., glutamine [FDR-corrected q-value = 0.0012]), glycerophospholipids (e.g., lysophosphatidylcholine 16:1 [q = 0.0008]), steroids (e.g., cortisone [q = 0.00001]), and fatty acids (e.g., palmitoleic acid [q = 0.0031]). The main finding was that after controlling for baseline levels of self-reported alcohol use and the biomarker of alcohol use, gamma-glutamyl transferase, and when compared to both alcohol-control and control-control group, the alcohol-case group had lower serum levels of asparagine (Cohen's d = -0.48 [95% CI -0.78 to -0.19] and d = -0.49 [-0.78 to -0.19], respectively) and serotonin (d = -0.45 [-0.74 to -0.15], and d = -0.46 [-0.75 to -0.16], respectively), with no difference between the two control groups (asparagine d = 0.00 [-0.29 to 0.29] and serotonin d = -0.01 [-0.30 to 0.29]). CONCLUSIONS: Changes in the circulating metabolome, especially lower serum levels of asparagine and serotonin, are associated with later diagnoses of alcohol-related diseases, even after adjustment for the baseline level of alcohol use.