Identification of Circulating Proteins Associated With Blood Pressure Using Mendelian Randomization.
Circ Genom Precis Med
; 13(1): e002605, 2020 02.
Article
de En
| MEDLINE
| ID: mdl-31928076
ABSTRACT
BACKGROUND:
Hypertension is a common modifiable risk factor for cardiovascular disease and mortality. Pathophysiological mechanisms leading to hypertension remain incompletely understood. Mendelian randomization (MR) allows the evaluation of the causal role of markers by minimizing the risk of biases such as reverse causation and confounding. We aimed to identify novel circulating proteins associated with blood pressure through a comprehensive screen of 227 blood biomarkers using MR.METHODS:
Genetic determinants of 227 biomarkers were identified in ORIGIN (Outcome Reduction With Initial Glargine Intervention; URL http//www.clinicaltrials.gov. Unique identifier NCT00069784) participants (N=4147) and combined with genetic effects on systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure from the International Consortium for Blood Pressure (74 064 individuals) using MR. Results were replicated in the UK Biobank (up to 319 103 individuals) and using another biomarker dataset (N=3301). MR analyses with cardiovascular risk factors and outcomes as well as other biomarkers were performed to further evaluate the mechanisms involved.RESULTS:
Six biomarkers were associated with blood pressure using MR after adjustment for multiple hypothesis testing. Relationships between NT-proBNP (N-terminal Pro-B-type natriuretic peptide), systolic blood pressure, and diastolic blood pressure confirmed previous reports. Novel circulating proteins associated with blood pressure were also identified. uPA (urokinase-type plasminogen activator) was related to systolic blood pressure; ADM (adrenomedullin) was related to systolic blood pressure and pulse pressure; IL (interleukin) 16 was related to diastolic blood pressure; cFn (cellular fibronectin) and IGFBP3 (insulin-like growth factor-binding protein 3) were related to pulse pressure. With the exception of IL16 and diastolic blood pressure (P=0.58), these relationships were validated in the UK Biobank (P<0.0001). Further MR analyses with cardiovascular risk factors and outcomes showed relationships between NT-proBNP and large-artery atherosclerotic stroke, IGFBP3 and diabetes mellitus as well as cFn and body mass index.CONCLUSIONS:
We identified novel biomarkers associated with blood pressure using MR. These markers could prove useful for risk assessment and as potential therapeutic targets.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Marqueurs biologiques
/
Maladies cardiovasculaires
/
Appréciation des risques
/
Polymorphisme de nucléotide simple
/
Diabète de type 2
/
Analyse de randomisation mendélienne
/
Hypertension artérielle
Type d'étude:
Clinical_trials
/
Diagnostic_studies
/
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limites:
Female
/
Humans
/
Male
/
Middle aged
Pays/Région comme sujet:
America do norte
Langue:
En
Journal:
Circ Genom Precis Med
Année:
2020
Type de document:
Article
Pays d'affiliation:
Canada