A Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension
A Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension
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孟德尔随机研究和临床随访将代谢物与肺动脉高压的风险和严重程度联系起来
DOI：
10.1101/2023.06.30.23292100
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Alhathli E
中科院分区：
文献类型：
--
作者：
Alhathli E
BackgroundPulmonary 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 ResultsUsing 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 tol‐proline betaine, which has previously been linked to modulation of inflammation and tissue remodeling in PAH. Our multivariable MR analysis suggests that the effect ofl‐proline betaine is actually mediated indirectly via homostachydrine.ConclusionsOur data present a method for study of the metabolome in the context of PAH, and suggests several candidates for further evaluation and translational research.
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影响因子：
7.7
作者：
Bowden J;Spiller W;Del Greco M F;Sheehan N;Thompson J;Minelli C;Davey Smith G
通讯作者：
Davey Smith G
影响因子：
64.8
作者：
Wang Q;Dhindsa RS;Carss K;Harper AR;Nag A;Tachmazidou I;Vitsios D;Deevi SVV;Mackay A;Muthas D;Hühn M;Monkley S;Olsson H;AstraZeneca Genomics Initiative;Wasilewski S;Smith KR;March R;Platt A;Haefliger C;Petrovski S
通讯作者：
Petrovski S
DOI：
10.1016/j.pnmrs.2017.01.001
发表时间：
2017-05
影响因子：
6.1
作者：
Marshall DD;Powers R
通讯作者：
Powers R
影响因子：
9.6
作者：
Benza, Raymond L.;Gomberg-Maitland, Mardi;Frantz, Robert P.
通讯作者：
Frantz, Robert P.
DOI：
10.1183/13993003.03201-2020
发表时间：
2021-04
期刊：
The European respiratory journal
影响因子：
--
作者：
Swietlik EM;Ghataorhe P;Zalewska KI;Wharton J;Howard LS;Taboada D;Cannon JE;UK National Cohort Study of PAH;Morrell NW;Wilkins MR;Toshner M;Pepke-Zaba J;Rhodes CJ
通讯作者：
Rhodes CJ