Nucleosides Associated With Incident Ischemic Stroke in the REGARDS and JHS Cohorts.

Case-Control Studies Coronary Disease Genome-Wide Association Study Guanosine Humans Incidence Ischemic Stroke Longitudinal Studies Nucleosides Pseudouridine Risk Factors Stroke / epidemiology

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
24 05 2022
Historique:
received: 04 08 2021
accepted: 04 02 2022
pubmed: 11 3 2022
medline: 26 5 2022
entrez: 10 3 2022
Statut: ppublish

Résumé

Both genetic and environmental factors contribute to stroke risk. We sought to identify novel metabolites associated with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort and determine whether they reflected genetic or environmental variation. This was a stroke case-cohort observational study nested in REGARDS. Cases were defined as incident stroke and metabolomic profiles were compared to a randomly selected control cohort. In baseline plasma samples, 162 metabolites were measured using liquid chromatography-tandem mass spectrometry. Cox proportional hazards models were adjusted for age, sex, race, and age by race in the base model. Fully adjusted models included traditional stroke risk factors. Mediation analyses conducted for these stroke risk factors used the metabolite as mediator. Genome-wide associations with the leading candidate metabolites were calculated using array data. Replication analyses in the Jackson Heart Study (JHS) were conducted using random effects meta-analysis. There were 2,043 participants who were followed over an average period of 7.1 years, including 1,075 stroke cases and 968 random controls. Nine metabolites were associated with stroke in the base model, 8 of which were measured and remained significant in meta-analysis with JHS. In the fully adjusted model in REGARDS, guanosine (hazard ratio [HR] 1.34, 95% CI 1.18-1.53; Guanosine and pseudouridine are nucleosides associated with incident ischemic stroke independently of other risk factors. Genetic and mediation analyses suggest that environmental exposures rather than genetic variation link nucleoside levels to stroke risk. This study provides Class II evidence that guanosine and pseudouridine are associated with incident stroke.

Sections du résumé

BACKGROUND AND OBJECTIVES
Both genetic and environmental factors contribute to stroke risk. We sought to identify novel metabolites associated with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort and determine whether they reflected genetic or environmental variation.
METHODS
This was a stroke case-cohort observational study nested in REGARDS. Cases were defined as incident stroke and metabolomic profiles were compared to a randomly selected control cohort. In baseline plasma samples, 162 metabolites were measured using liquid chromatography-tandem mass spectrometry. Cox proportional hazards models were adjusted for age, sex, race, and age by race in the base model. Fully adjusted models included traditional stroke risk factors. Mediation analyses conducted for these stroke risk factors used the metabolite as mediator. Genome-wide associations with the leading candidate metabolites were calculated using array data. Replication analyses in the Jackson Heart Study (JHS) were conducted using random effects meta-analysis.
RESULTS
There were 2,043 participants who were followed over an average period of 7.1 years, including 1,075 stroke cases and 968 random controls. Nine metabolites were associated with stroke in the base model, 8 of which were measured and remained significant in meta-analysis with JHS. In the fully adjusted model in REGARDS, guanosine (hazard ratio [HR] 1.34, 95% CI 1.18-1.53;
DISCUSSION
Guanosine and pseudouridine are nucleosides associated with incident ischemic stroke independently of other risk factors. Genetic and mediation analyses suggest that environmental exposures rather than genetic variation link nucleoside levels to stroke risk.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that guanosine and pseudouridine are associated with incident stroke.

Identifiants

DOI: 10.1212/WNL.0000000000200262 PMID: 35264422 PMC: PMC9169945
pubmed: 35264422
pii: WNL.0000000000200262
doi: 10.1212/WNL.0000000000200262
pmc: PMC9169945
doi:

Substances chimiques

Nucleosides 0
Guanosine 12133JR80S
Pseudouridine 1445-07-4

Types de publication

Journal Article Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2097-e2107

Subventions

Organisme : NIGMS NIH HHS
ID : P20 GM135007
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS041588
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800010I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800012I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800011I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800014I
Pays : United States
Organisme : NIMHD NIH HHS
ID : HHSN268201800013I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800015I
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS099209
Pays : United States

Informations de copyright

© 2022 American Academy of Neurology.

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Auteurs

Zsuzsanna Ament (Z)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
ORCID: 0000-0002-0316-4348

Amit Patki (A)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.

Ninad Chaudhary (N)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
ORCID: 0000-0003-1350-1093

Varun M Bhave (VM)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.

Ana-Lucia Garcia Guarniz (AL)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.

Yan Gao (Y)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.

Robert E Gerszten (RE)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.

Adolfo Correa (A)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
ORCID: 0000-0002-9501-600X

Suzanne E Judd (SE)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
ORCID: 0000-0001-7594-6587

Mary Cushman (M)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
ORCID: 0000-0002-7871-6143

D Leann Long (DL)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
ORCID: 0000-0001-8614-7190

M Ryan Irvin (MR)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.

W Taylor Kimberly (WT)

From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
ORCID: 0000-0002-2519-8530

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Classifications MeSH

questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Ischémie myocardique › Maladie coronarienne › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Guanosine › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Registre civil › Morbidité › Incidence › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Angiopathies intracrâniennes › Accident vasculaire cérébral › Accident vasculaire cérébral ischémique › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études longitudinales › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Uridine › Pseudouridine › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Nucleosides Associated With Incident Ischemic...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Angiopathies intracrâniennes › Accident vasculaire cérébral › Nucleosides Associated With Incident Ischemic...