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A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk
M. Ferrell, Z. Wang, JT. Anderson, XS. Li, M. Witkowski, JA. DiDonato, JR. Hilser, JA. Hartiala, A. Haghikia, T. Cajka, O. Fiehn, N. Sangwan, I. Demuth, M. König, E. Steinhagen-Thiessen, U. Landmesser, WHW. Tang, H. Allayee, SL. Hazen
Jazyk angličtina Země Spojené státy americké
Typ dokumentu metaanalýza, časopisecké články
Grantová podpora
R01 HL103866
NHLBI NIH HHS - United States
P01 HL147823
NHLBI NIH HHS - United States
T32 HL134622
NHLBI NIH HHS - United States
T32 GM007250
NIGMS NIH HHS - United States
R01 HL133169
NHLBI NIH HHS - United States
R01 HL148110
NHLBI NIH HHS - United States
R01 HL103866
NHLBI NIH HHS - United States
P01 HL147823
NHLBI NIH HHS - United States
T32 HL134622
NHLBI NIH HHS - United States
T32 GM007250
NIGMS NIH HHS - United States
R01 HL133169
NHLBI NIH HHS - United States
R01 HL148110
NHLBI NIH HHS - United States
- MeSH
- kardiovaskulární nemoci * MeSH
- lidé MeSH
- myši MeSH
- niacin * MeSH
- proporcionální rizikové modely MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
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.
Berlin Institute of Health Berlin Germany
Berlin Institute of Health Center for Regenerative Therapies Berlin Germany
Department of Endocrinology and Metabolism Charité Universitätsmedizin Berlin Berlin Germany
Friede Springer Cardiovascular Prevention Center at Charité Berlin Germany
German Center for Cardiovascular Research Partner Site Berlin Berlin Germany
Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
West Coast Metabolomics Center University of California Davis Davis CA USA
Citace poskytuje Crossref.org
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- $a A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk / $c M. Ferrell, Z. Wang, JT. Anderson, XS. Li, M. Witkowski, JA. DiDonato, JR. Hilser, JA. Hartiala, A. Haghikia, T. Cajka, O. Fiehn, N. Sangwan, I. Demuth, M. König, E. Steinhagen-Thiessen, U. Landmesser, WHW. Tang, H. Allayee, SL. Hazen
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- $a 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.
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