Alhathli, E. orcid.org/0009-0008-2147-9715, Julian, T. orcid.org/0000-0002-5488-5620, Girach, Z.U.A. et al. (8 more authors) (2024) Mendelian randomization study with clinical follow‐up links metabolites to risk and severity of pulmonary arterial hypertension. Journal of the American Heart Association, 13 (6). e032256. ISSN: 2047-9980
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/ |
Keywords: | Mendelian randomization; homostachydrine; metabolome; pulmonary arterial hypertension; serine; Humans; Pulmonary Arterial Hypertension; Genome-Wide Association Study; Mendelian Randomization Analysis; Follow-Up Studies; Familial Primary Pulmonary Hypertension; Serine |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/K020919/1 BRITISH HEART FOUNDATION FS/18/13/33281 WELLCOME TRUST (THE) 216596/Z/19/Z BRITISH HEART FOUNDATION FS/18/52/33808 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 19 Sep 2025 10:14 |
Last Modified: | 19 Sep 2025 10:14 |
Status: | Published |
Publisher: | Ovid Technologies (Wolters Kluwer Health) |
Refereed: | Yes |
Identification Number: | 10.1161/jaha.123.032256 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:231903 |