Pharmacometabolomics of statin response.
Ontology highlight
ABSTRACT:
SUBMITTER: Krauss RM
PROVIDER: S-EPMC4055080 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
Publications
Pharmacometabolomics of statin response.
Krauss R M RM Zhu H H Kaddurah-Daouk R R
Clinical pharmacology and therapeutics 20130814 5
Statins reduce risk of cardiovascular disease (CVD) by decreasing plasma low-density lipoprotein (LDL) concentrations, as well as reducing inflammation and improving endothelial function. Despite their documented efficacy, there is considerable interindividual variation in effects of statins on CVD biomarkers. In the studies summarized here, we used complementary metabolomics platforms to define global effects of a statin (simvastatin) on metabolism and to identify markers indicative of mechanis ...[more]
Similar Datasets
Project description:Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.
| S-EPMC3594230 | biostudies-literature
Project description:While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81?mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72?±?8 vs. 61?±?11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9?×?10(-4), N = 12). These results suggest that serotonin is implicated in aspirin response variability.
| S-EPMC4120016 | biostudies-literature
Project description:The initial decades of the 21st century have witnessed striking technical advances that have made it possible to detect, identify and quantitatively measure large numbers of plasma or tissue metabolites. In parallel, similar advances have taken place in our ability to sequence DNA and RNA. Those advances have moved us beyond studies of single metabolites and single genetic polymorphisms to the study of hundreds or thousands of metabolites and millions of genomic variants in a single cell or subject. It is now possible to merge and integrate large data sets generated by the use of different "-omics" techniques to increase our understanding of the molecular basis for variation in disease risk and/or drug response phenotypes. This "Brief Review" will outline some of the challenges and opportunities associated with studies in which metabolomic data have been merged with genomics in an attempt to gain novel insight into mechanisms associated with variation in drug response phenotypes, with an emphasis on the application of a pharmacometabolomics-informed pharmacogenomic research strategy and with selected examples of the application of that strategy. Studies that used pharmacometabolomics to inform and guide pharmacogenomics were reviewed. Clinical studies that were used as the basis for pharmacometabolomics-informed pharmacogenomic studies, published in five independent manuscripts, are described briefly. Within these five manuscripts, both pharmacokinetic and pharmacodynamic metabolomics approaches were used. Candidate gene and genome-wide approaches that were used in concert with these metabolomic data identified novel metabolite-gene relationships that were associated with drug response phenotypes in these pharmacometabolomics-informed pharmacogenomics studies. This "Brief Review" outlines the emerging discipline of pharmacometabolomics-informed pharmacogenomics in which metabolic profiles are associated with both clinical phenotypes and genetic variants to identify novel genetic variants associated with drug response phenotypes based on metabolic profiles.
| S-EPMC4976774 | biostudies-literature
Project description:Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis.To use existing serum samples from the phase 1 clinical trial of l-carnitine treatment for severe sepsis to metabolically phenotype l-carnitine responders and nonresponders.Serum samples collected before (T0) and after completion of the infusion (T24, T48) from patients randomized to either l-carnitine (12 g) or placebo for the treatment of vasopressor-dependent septic shock were assayed by untargeted (1)H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of l-carnitine- and placebo-treated patients at each time point were compared by analysis of variance with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks.Thirty-eight metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, and 3-hydroxyisovalerate were different at T0 and over time in l-carnitine-treated survivors versus nonsurvivors. Pathway analysis of pretreatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating l-carnitine treatment response. Analysis of all patients based on pretreatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153 ?M), patients were categorized as either high or low ketone. l-Carnitine-treated low-ketone patients had greater use of carnitine as evidenced by lower post-treatment l-carnitine levels. The l-carnitine responders also had faster resolution of vasopressor requirement and a trend toward a greater improvement in mortality at 1 year (P = 0.038) compared with patients with higher 3-hydroxybutyrate.The results of this preliminary study, which were not readily apparent from the parent clinical trial, show a unique metabolite profile of l-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing l-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study.
| S-EPMC4342803 | biostudies-literature
Project description:The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (p-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: β = -0.004, p = 1.8 × 10-4; GACRS: β = -0.015, p = 0.018), and a cholesterol ester; CE C18:1 (CAMP: β = 0.005, p = 0.006; GACRS: β = 0.023, p = 0.041) Five additional metabolites had a p-value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response.
| S-EPMC6780678 | biostudies-literature
Project description:We have previously identified a number of statin-responsive genes in human cell lines, but in some cases, these findings may not be relevant in vivo. Here, we statin exposed primary human hepatocytes from four different donors to identify statin-responsive genes in this biologically relevant cell type. We also compared the effects of statin on gene expression between these primary cells and our previous datasets in other cell lines to identify overlapping effects of interest.
2024-12-16 | GSE191092 | GEO
Project description:A prospective cohort study was performed in preterm infants less than 32 weeks gestation at birth who were treated with dexamethasone for developing or established bronchopulmonary dysplasia (BPD). Respiratory phenotype (Respiratory Severity Score (RSS)), serum, and urine metabolomics were assessed before and after treatment. Ten infants provided nine matched serum and nine matched urine samples. There was a significant decrease in RSS with steroid treatment. Serum gluconic acid had the largest median fold change (140 times decreased, P = 0.008). In metabolite set enrichment analysis, in both serum and urine, the urea cycle, ammonia recycling, and malate-aspartate shuttle pathways were most significantly enriched when comparing pretreatment and post-treatment (P value < 0.05). In regression analyses, 6 serum and 28 urine metabolites were significantly associated with change in RSS. Urine gluconic acid lactone was the most significantly correlated with clinical response (correlational coefficient 0.915). Pharmacometabolomic discovery of drug response biomarkers in preterm infants may allow precision therapeutics in BPD treatment.
| S-EPMC6853142 | biostudies-literature
Project description:Inter-individual variability has been a major hurdle to optimize disease management. Precision medicine holds promise for improving health and healthcare via tailor-made therapeutic strategies. Herein, we outline the paradigm of "pharmacometabolomics-aided pharmacogenomics" in autoimmune diseases. We envisage merging pharmacometabolomic and pharmacogenomic data (to address the interplay of genomic and environmental influences) with information technologies to facilitate data analysis as well as sense- and decision-making on the basis of synergy between artificial and human intelligence. Humans can detect patterns, which computer algorithms may fail to do so, whereas data-intensive and cognitively complex settings and processes limit human ability. We propose that better-informed, rapid and cost-effective omics studies need the implementation of holistic and multidisciplinary approaches.
| S-EPMC4816847 | biostudies-literature
Project description:Primary human hepatocyte transcriptomic statin response
| PRJNA789648 | ENA
Project description:Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n?=?35) or placebo (n?=?40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, ?(2)(1) ?=?0.75, p?=?0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.
| S-EPMC3714282 | biostudies-literature