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.