| Title: | A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk |
| Journal: | Nature Medicine |
| Published: | 19 Feb 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38374343/ |
| DOI: | https://doi.org/10.1038/s41591-023-02793-8 |
Publication 8714
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10−18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10−5; 4PY: rho = 0.18, P = 1.1 × 10−8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.</p>
19 Authors
- Marc Ferrell
- Zeneng Wang
- James T. Anderson
- Xinmin S. Li
- Marco Witkowski
- Joseph A. DiDonato
- James R. Hilser
- Jaana A. Hartiala
- Arash Haghikia
- Tomas Cajka
- Oliver Fiehn
- Naseer Sangwan
- Ilja Demuth
- Maximilian König
- Elisabeth Steinhagen-Thiessen
- Ulf Landmesser
- W. H. Wilson Tang
- Hooman Allayee
- Stanley L. Hazen
1 Application
| Application ID | Title |
|---|---|
| 33307 | Sex-specific Genetic Determinants of Cardiometabolic Traits |
Enabling scientific discoveries that improve human health