Mendelian Randomization Study With Clinical Follow-Up Links Metabolites to Risk and Severity of Pulmonary Arterial Hypertension.

Autor: Alhathli E; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield Sheffield UK.; Department of Nursing, Faculty of Applied Medical Sciences Taif University Taif Saudi Arabia., Julian T; Division of Evolution, Infection and Genomics, School of Biological Sciences The University of Manchester Manchester UK., Girach ZUA; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield Sheffield UK., Thompson AAR; Department of Infection, Immunity and Cardiovascular Disease University of Sheffield Sheffield UK., Rhodes C; National Heart and Lung Institute, Imperial College London London UK., Gräf S; Department of Respiratory Medicine University of Cambridge Cambridge UK., Errington N; National Heart and Lung Institute, Imperial College London London UK., Wilkins MR; National Heart and Lung Institute, Imperial College London London UK., Lawrie A; National Heart and Lung Institute, Imperial College London London UK., Wang D; Department of Computer Science University of Sheffield Sheffield UK.; National Heart and Lung Institute, Imperial College London London UK.; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR) Singapore Republic of Singapore., Cooper-Knock J; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield Sheffield UK.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2024 Mar 19; Vol. 13 (6), pp. e032256. Date of Electronic Publication: 2024 Mar 08.
DOI: 10.1161/JAHA.123.032256
Abstrakt: Background: Pulmonary arterial hypertension (PAH) exhibits phenotypic heterogeneity and variable response to therapy. The metabolome has been implicated in the pathogenesis of PAH, but previous works have lacked power to implicate specific metabolites. Mendelian randomization (MR) is a method for causal inference between exposures and outcomes.
Methods and Results: Using genome-wide association study summary statistics, we implemented MR analysis to test for potential causal relationships between serum concentration of 575 metabolites and PAH. Five metabolites were causally associated with the risk of PAH after multiple testing correction. Next, we measured serum concentration of candidate metabolites in an independent clinical cohort of 449 patients with PAH to check whether metabolite concentrations are correlated with markers of disease severity. Of the 5 candidates nominated by our MR work, serine was negatively associated and homostachydrine was positively associated with clinical severity of PAH via direct measurement in this independent clinical cohort. Finally we used conditional and orthogonal approaches to explore the biology underlying our lead metabolites. Rare variant burden testing was carried out using whole exome sequencing data from 578 PAH cases and 361 675 controls. Multivariable MR is an extension of MR that uses a single set of instrumental single-nucleotide polymorphisms to measure multiple exposures; multivariable MR is used to determine interdependence between the effects of different exposures on a single outcome. Rare variant analysis demonstrated that loss-of-function mutations within activating transcription factor 4, a transcription factor responsible for upregulation of serine synthesis under conditions of serine starvation, are associated with higher risk for PAH. Homostachydrine is a xenobiotic metabolite that is structurally related to l-proline betaine, which has previously been linked to modulation of inflammation and tissue remodeling in PAH. Our multivariable MR analysis suggests that the effect of l-proline betaine is actually mediated indirectly via homostachydrine.
Conclusions: Our data present a method for study of the metabolome in the context of PAH, and suggests several candidates for further evaluation and translational research.
Databáze: MEDLINE
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