Affiliation:
1. Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health Tongji Medical College, Huazhong University of Science and Technology Wuhan China
2. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian China
3. University of Chinese Academy of Sciences Beijing China
4. Division of Epidemiology, Department of Medicine Vanderbilt University Medical Center Nashville TN
5. Department of Cardiovascular Disease, Sinopharm Dongfeng Central Hospital Hubei University of Medicine Shiyan China
Abstract
Background
This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations.
Methods and Results
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
P
=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
P
=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
P
=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 (
P
‐trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (
P
<0.05), supported by its causal links with hypertension (
P
<0.05) and hypertriglyceridemia (
P
=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],
P
=0.036), yet the association was nonsignificant when further adjusting for fasting glucose.
Conclusions
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine