초록
<P>Background<P>This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations.</P></P><P>Methods and Results<P> We performed nontargeted metabolomics in a nested case‐control study in the Dongfeng‐Tongji cohort, including 500 incident ACS cases and 500 age‐ and sex‐matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5‐anhydro‐ d ‐glucitol (1,5‐AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut‐brain peptide cholecystokinin‐8 rather than angiotensin by the angiotensin‐converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted <I>P</I> =0.025), 1,5‐AG is a marker of short‐term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted <I>P</I> =0.025), and tetracosanoic acid is a very‐long‐chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted <I>P</I> =0.091). Similar associations of 1,5‐AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors ( <I>P</I> ‐trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia ( <I>P</I> <0.05), supported by its causal links with hypertension ( <I>P</I> <0.05) and hypertriglyceridemia ( <I>P</I> =0.077) in Mendelian randomization analysis. The association of 1,5‐AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5‐AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], <I>P</I> =0.036), yet the association was nonsignificant when further adjusting for fasting glucose. </P></P><P>Conclusions<P>These findings highlighted novel angiotensin‐independent involvement of the angiotensin‐converting enzyme in ACS cause, and the importance of glycemic excursions and very‐long‐chain saturated fatty acid metabolism.</P></P>