Serum Metabolomic Profiling of All-Cause Mortality: A Prospective Analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study Cohort

Abstract

Tobacco use, hypertension, hyperglycemia, overweight, and inactivity are leading causes of overall and cardiovascular disease (CVD) mortality worldwide, yet the relevant metabolic alterations responsible are largely unknown. We conducted a serum metabolomic analysis of 620 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-2013). During 28 years of follow-up, there were 435 deaths (197 CVD and 107 cancer). The analysis included 406 known metabolites measured with ultra-high performance liquid chromatography/mass spectrometry-gas chromatography/mass spectrometry. Cox regression estimated mortality hazard ratios (HR) for a one standard-deviation difference in metabolite-signals, and we divided the data into training and test-sets, creating a metabolite risk score of the strongest metabolites in the former to test in the latter. The strongest associations with overall mortality were N-acetylvaline (HR=1.28; P<4.1×10^-5, below Bonferroni statistical threshold), and dimethylglycine, 7-methylguanine, C-glycosyltryptophan, taurocholate, and N-acetyltryptophan (1.23≤HR≤1.32; 5×10^-5≤P≤1×10^-4). C-Glycosyltryptophan, 7-methylguanine, and 4-androsten-3beta,17beta-diol disulfate were statistically significantly associated with CVD mortality (1.49≤HR≤1.62, P<4.1×10^-5). No metabolite was associated with cancer mortality at false discovery rate<0.1. Individuals with a one standard-deviation higher metabolite risk score had increased all-cause and CVD mortality in the test-set (HR=1.4, P=0.05; HR=1.8, P=0.003, respectively). The several serum metabolites and their composite risk score independently associated with all-cause and CVD mortality may provide potential leads regarding the molecular basis of mortality.