Metabolomics Signature of Plasma Renin Activity and Linkage with Blood Pressure Response to Beta Blockers and Thiazide Diuretics in Hypertensive European American Patients

Mehanna, Mai; McDonough, Caitrin W.; Smith, Steven M.; Gong, Yan; Gums, John G.; Chapman, Arlene B.; McIntyre, Lauren; Cooper‐DeHoff, Rhonda M.

doi:10.3390/metabo11090645

Cited by 10 publications

(12 citation statements)

References 53 publications

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“…The other three metabolites (X‐21735, X‐24309 and X‐21849) are largely unknown. As previously reported, levels of xenobiotic X‐21735 were higher in early stage Parkinson disease cases compared with matched controls 42 and X‐24309 was associated with the baseline plasma renin activity (PRA) in antihypertensive responses‐2 (PEAR‐2) European Americans 43 . Although metabolite identification remains the bottleneck in untargeted metabolomics field, our results add to a growing body of research that provides important clues to the relationship between unknown metabolites and human diseases.…”

Section: Discussionsupporting

confidence: 77%

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Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk

Zhong

Liu

Zhu

et al. 2023

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, which is featured by systematic metabolism. Thus, a better understanding of metabolic dysregulation in PDAC is important to better characterize its etiology. Here, we performed a large metabolome-wide association study (MWAS) to systematically explore associations between genetically predicted metabolite levels in blood and PDAC risk. Using data from 881 subjects of European descent in the TwinsUK Project, comprehensive genetic models were built to predict serum metabolite levels. These prediction models were applied to the genetic data of 8275 cases and 6723 controls included in the PanScan (I, II and III) and PanC4 consortia. After assessing the metabolite-PDAC risk associations by a slightly modified TWAS/FUSION framework, we identified five metabolites (including two dipeptides) showing significant associations with PDAC risk at false discovery rate (FDR) <0.05. Integrated with gut microbial information, two-sample Mendelian randomization (MR) analyses were further performed to investigate the relationship among serum metabolites, gut microbiome features and PDAC. The flavonoid-degrading bacteria Flavonifractor sp90199495 was found to be associated with metabolite X-21849 and it was also shown to be associated with PDAC risk. Collectively, our study identified novel candidate metabolites for PDAC risk, which could lead to new insights into the etiology of PDAC and improved treatment options.

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Section: Discussionsupporting

confidence: 77%

“…40,41 The other three in antihypertensive responses-2 (PEAR-2) European Americans. 43 Although metabolite identification remains the bottleneck in untargeted metabolomics field, our results add to a growing body of research that provides important clues to the relationship between unknown metabolites and human diseases.…”

Section: Discussionmentioning

confidence: 84%

Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk

Zhong

Liu

Zhu

et al. 2023

Intl Journal of Cancer

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“…5,6 We previously identified and replicated eight known metabolites associated with baseline PRA among two cohorts of European American hypertensive participants. 7 Additionally, we identified and replicated four metabolic clusters significantly different between hypertensive participants with lower versus higher %GWAA. 8 As PRA and %GWAA are key interconnected factors affecting BP response to TDs and BBs, we sought to identify the commonly shared canonical pathways between our metabolic signals associated with PRA and %GWAA using an integrated metabolomics analysis.…”

Section: Introductionmentioning

confidence: 72%

“…These 47 metabolic signals are organized into two sets, based on our previous work. The first set consists of all the replicated, known metabolites associated with baseline PRA in European American hypertensive participants ( n = 8) 7 . All eight metabolites, except gamma‐glutamylglutamine, are positively correlated with higher baseline PRA.…”

Section: Methodsmentioning

confidence: 99%

Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers

Mehanna,

McDonough,

Smith

et al. 2024

Clinical Translational Sci

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Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to β‐blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP‐lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR‐2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1‐ phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD‐ and BB‐induced vasodilatation. These findings may improve our understanding of the BP‐lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP‐lowering effects from these drugs.

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“…Moreover, only losartan reduced sphingomyelinase-induced contractions of isolated carotid arteries, which may result from the reduction in the endothelial expression of calcium-independent phospholipase A2 ( 48 ). Furthermore, S1P has been associated with a higher baseline plasma renin activity and a reduced blood pressure response to hydrochlorothiazide (thiazide diuretic) in hypertensive patients ( 49 ).…”

Section: Sphingolipids In Cardiovascular Diseasesmentioning

confidence: 99%

Sphingolipid metabolism and signaling in cardiovascular diseases

Borodzicz-Jażdżyk

Jażdżyk

Łysik

et al. 2022

Front. Cardiovasc. Med.

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Sphingolipids are a structural component of the cell membrane, derived from sphingosine, an amino alcohol. Its sphingoid base undergoes various types of enzymatic transformations that lead to the formation of biologically active compounds, which play a crucial role in the essential pathways of cellular signaling, proliferation, maturation, and death. The constantly growing number of experimental and clinical studies emphasizes the pivotal role of sphingolipids in the pathophysiology of cardiovascular diseases, including, in particular, ischemic heart disease, hypertension, heart failure, and stroke. It has also been proven that altering the sphingolipid metabolism has cardioprotective properties in cardiac pathologies, including myocardial infarction. Recent studies suggest that selected sphingolipids may serve as valuable biomarkers useful in the prognosis of cardiovascular disorders in clinical practice. This review aims to provide an overview of the current knowledge of sphingolipid metabolism and signaling in cardiovascular diseases.

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Metabolomics Signature of Plasma Renin Activity and Linkage with Blood Pressure Response to Beta Blockers and Thiazide Diuretics in Hypertensive European American Patients

Cited by 10 publications

References 53 publications

Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk

Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk

Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers

Sphingolipid metabolism and signaling in cardiovascular diseases

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