Imperial College London
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ProfessorDennisWang

Faculty of Medicine, National Heart & Lung Institute

Chair in Data Science
 
 
 
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dennis.wang CV

 
 
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Location

 

Sir Michael Uren HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Alhathli:2024:10.1161/JAHA.123.032256,
author = {Alhathli, E and Julian, T and Girach, ZUA and Thompson, AAR and Rhodes, C and Gräf, S and Errington, N and Wilkins, MR and Lawrie, A and Wang, D and Cooper-Knock, J},
doi = {10.1161/JAHA.123.032256},
journal = {Journal of the American Heart Association},
title = {Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension},
url = {http://dx.doi.org/10.1161/JAHA.123.032256},
volume = {13},
year = {2024}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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
AU  - Alhathli,E
AU  - Julian,T
AU  - Girach,ZUA
AU  - Thompson,AAR
AU  - Rhodes,C
AU  - Gräf,S
AU  - Errington,N
AU  - Wilkins,MR
AU  - Lawrie,A
AU  - Wang,D
AU  - Cooper-Knock,J
DO  - 10.1161/JAHA.123.032256
PY  - 2024///
SN  - 2047-9980
TI  - Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension
T2  - Journal of the American Heart Association
UR  - http://dx.doi.org/10.1161/JAHA.123.032256
UR  - https://www.ncbi.nlm.nih.gov/pubmed/38456412
UR  - https://www.ahajournals.org/doi/10.1161/JAHA.123.032256
UR  - http://hdl.handle.net/10044/1/110251
VL  - 13
ER  -
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