ABSTRACT
Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the TwinsUK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.
Subject(s)
Biomarkers/analysis , Genetic Loci , Genome-Wide Association Study , Metabolome , Polymorphism, Single Nucleotide , Saliva/chemistry , Saliva/metabolism , Cohort Studies , Computational Biology , Female , Humans , Male , Metabolic Networks and Pathways , Middle AgedABSTRACT
RATIONALE & OBJECTIVE: Stratification of chronic kidney disease (CKD) patients at risk for progressing to kidney failure requiring kidney replacement therapy (KFRT) is important for clinical decision-making and trial enrollment. STUDY DESIGN: Four independent prospective observational cohort studies. SETTING & PARTICIPANTS: The development cohort comprised 4,915 CKD patients, and 3 independent validation cohorts comprised a total of 3,063. Patients were observed for approximately 5 years. EXPOSURE: 22 demographic, anthropometric, and laboratory variables commonly assessed in CKD patients. OUTCOME: Progression to KFRT. ANALYTICAL APPROACH: A least absolute shrinkage and selection operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for KFRT. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation both in a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs. RESULTS: The newly derived 6-variable risk score (Z6) included serum creatinine, albumin, cystatin C, and urea, as well as hemoglobin and the urinary albumin-creatinine ratio. In the the resampling approach, Z6 achieved a median C statistic of 0.909 (95% CI, 0.868-0.937) at 2 years after the baseline visit, whereas the T4 achieved a median C statistic of 0.855 (95% CI, 0.799-0.915). In the 3 independent validation cohorts, the Z6C statistics were 0.894, 0.921, and 0.891, whereas the T4C statistics were 0.882, 0.913, and 0.862. LIMITATIONS: The Z6 was both derived and tested only in White European cohorts. CONCLUSIONS: A new risk equation based on 6 routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to KFRT.
Subject(s)
Kidney Failure, Chronic , Renal Insufficiency, Chronic , Renal Insufficiency , Disease Progression , Glomerular Filtration Rate , Humans , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiologyABSTRACT
Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. SLC22A1 encodes a hepatic plasma membrane transporter whose role in acylcarnitine physiology has not been described. By targeted metabolomics and isotope tracing experiments in loss- and gain-of-function cell and mouse models of Slc22a1, we uncovered a role of SLC22A1 in the efflux of acylcarnitines from the liver to the circulation. We further validated the impacts of human variants on SLC22A1-mediated acylcarnitine efflux in vitro, explaining their association with serum acylcarnitine levels. Our findings provide the detailed molecular mechanisms of the GWAS association for serum acylcarnitines at the SLC22A1 locus by functionally validating the impact of SLC22A1 and its variants on acylcarnitine transport.
Subject(s)
Carnitine/analogs & derivatives , Gene Expression Regulation , Liver/metabolism , Metabolic Diseases/genetics , Organic Cation Transporter 1/genetics , Polymorphism, Single Nucleotide , Alleles , Alternative Splicing , Animals , Biological Transport , CRISPR-Cas Systems , Carnitine/blood , Carnitine/pharmacokinetics , Cells, Cultured , Cohort Studies , Female , Genome-Wide Association Study , High-Throughput Nucleotide Sequencing , Humans , Male , Metabolic Diseases/blood , Metabolic Diseases/metabolism , Metabolomics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Organic Cation Transporter 1/antagonists & inhibitors , Organic Cation Transporter 1/metabolism , Tissue DistributionABSTRACT
MOTIVATION: The identification of protein targets of novel compounds is essential to understand compounds' mechanisms of action leading to biological effects. Experimental methods to determine these protein targets are usually slow, costly and time consuming. Computational tools have recently emerged as cheaper and faster alternatives that allow the prediction of targets for a large number of compounds. RESULTS: Here, we present HitPickV2, a novel ligand-based approach for the prediction of human druggable protein targets of multiple compounds. For each query compound, HitPickV2 predicts up to 10 targets out of 2739 human druggable proteins. To that aim, HitPickV2 identifies the closest, structurally similar compounds in a restricted space within a vast chemical-protein interaction area, until 10 distinct protein targets are found. Then, HitPickV2 scores these 10 targets based on three parameters of the targets in such space: the Tanimoto coefficient (Tc) between the query and the most similar compound interacting with the target, a target rank that considers Tc and Laplacian-modified naïve Bayesian target models scores and a novel parameter introduced in HitPickV2, the number of compounds interacting with each target (occur). We present the performance results of HitPickV2 in cross-validation as well as in an external dataset. AVAILABILITY AND IMPLEMENTATION: HitPickV2 is available in www.hitpickv2.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Software , Bayes Theorem , Humans , Ligands , ProteinsABSTRACT
BACKGROUND: Untargeted mass spectrometry (MS)-based metabolomics data often contain missing values that reduce statistical power and can introduce bias in biomedical studies. However, a systematic assessment of the various sources of missing values and strategies to handle these data has received little attention. Missing data can occur systematically, e.g. from run day-dependent effects due to limits of detection (LOD); or it can be random as, for instance, a consequence of sample preparation. METHODS: We investigated patterns of missing data in an MS-based metabolomics experiment of serum samples from the German KORA F4 cohort (n = 1750). We then evaluated 31 imputation methods in a simulation framework and biologically validated the results by applying all imputation approaches to real metabolomics data. We examined the ability of each method to reconstruct biochemical pathways from data-driven correlation networks, and the ability of the method to increase statistical power while preserving the strength of established metabolic quantitative trait loci. RESULTS: Run day-dependent LOD-based missing data accounts for most missing values in the metabolomics dataset. Although multiple imputation by chained equations performed well in many scenarios, it is computationally and statistically challenging. K-nearest neighbors (KNN) imputation on observations with variable pre-selection showed robust performance across all evaluation schemes and is computationally more tractable. CONCLUSION: Missing data in untargeted MS-based metabolomics data occur for various reasons. Based on our results, we recommend that KNN-based imputation is performed on observations with variable pre-selection since it showed robust results in all evaluation schemes.
Subject(s)
Mass Spectrometry , Metabolomics/methods , Chromatography, Liquid , Cohort Studies , GermanyABSTRACT
A metabolome-wide genome-wide association study (mGWAS) aims to discover the effects of genetic variants on metabolome phenotypes. Most mGWASes use as phenotypes concentrations of limited sets of metabolites that can be identified and quantified from spectral information. In contrast, in an untargeted mGWAS both identification and quantification are forgone and, instead, all measured metabolome features are tested for association with genetic variants. While the untargeted approach does not discard data that may have eluded identification, the interpretation of associated features remains a challenge. To address this issue, we developed metabomatching to identify the metabolites underlying significant associations observed in untargeted mGWASes on proton NMR metabolome data. Metabomatching capitalizes on genetic spiking, the concept that because metabolome features associated with a genetic variant tend to correspond to the peaks of the NMR spectrum of the underlying metabolite, genetic association can allow for identification. Applied to the untargeted mGWASes in the SHIP and CoLaus cohorts and using 180 reference NMR spectra of the urine metabolome database, metabomatching successfully identified the underlying metabolite in 14 of 19, and 8 of 9 associations, respectively. The accuracy and efficiency of our method make it a strong contender for facilitating or complementing metabolomics analyses in large cohorts, where the availability of genetic, or other data, enables our approach, but targeted quantification is limited.
Subject(s)
Databases, Genetic , Genome-Wide Association Study/methods , Magnetic Resonance Spectroscopy/methods , Metabolomics/methods , HumansABSTRACT
Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases.
Subject(s)
Genome-Wide Association Study , Metabolomics , Urine , Chromosome Mapping , Genetic Predisposition to Disease , Humans , Proton Magnetic Resonance Spectroscopy , Quantitative Trait LociABSTRACT
Genome-wide association studies with metabolomics (mGWAS) identify genetically influenced metabotypes (GIMs), their ensemble defining the heritable part of every human's metabolic individuality. Knowledge of genetic variation in metabolism has many applications of biomedical and pharmaceutical interests, including the functional understanding of genetic associations with clinical end points, design of strategies to correct dysregulations in metabolic disorders and the identification of genetic effect modifiers of metabolic disease biomarkers. Furthermore, it has been shown that GIMs provide testable hypotheses for functional genomics and metabolomics and for the identification of novel gene functions and metabolite identities. mGWAS with growing sample sizes and increasingly complex metabolic trait panels are being conducted, allowing for more comprehensive and systems-based downstream analyses. The generated large datasets of genetic associations can now be mined by the biomedical research community and provide valuable resources for hypothesis-driven studies. In this review, we provide a brief summary of the key aspects of mGWAS, followed by an update of recently published mGWAS. We then discuss new approaches of integrating and exploring mGWAS results and finish by presenting selected applications of GIMs in recent studies.
Subject(s)
Genome-Wide Association Study , Metabolism , Metabolome , Animals , Genetic Variation , Humans , Metabolic Networks and PathwaysABSTRACT
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
Subject(s)
Biomedical Research , Drug Industry , Genetic Variation , Genome-Wide Association Study , Metabolism/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Blood/metabolism , Child , Chronic Disease , Coronary Artery Disease/genetics , Diabetes Mellitus/genetics , Female , Genetic Loci/genetics , Genotype , Humans , Male , Metabolomics , Middle Aged , Pharmacogenetics , Renal Insufficiency/genetics , Risk Factors , Venous Thromboembolism/genetics , Young AdultABSTRACT
MOTIVATION: Linking genes and functional information to genetic variants identified by association studies remains difficult. Resources containing extensive genomic annotations are available but often not fully utilized due to heterogeneous data formats. To enhance their accessibility, we integrated many annotation datasets into a user-friendly webserver. AVAILABILITY AND IMPLEMENTATION: http://www.snipa.org/ CONTACT: g.kastenmueller@helmholtz-muenchen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Databases, Genetic , Genetic Variation/genetics , Genome, Human , Genomics/methods , Molecular Sequence Annotation , Software , HumansABSTRACT
Genome-wide association studies with concentrations of hundreds of small molecules in samples collected from thousands of individuals (mGWAS) access otherwise inaccessible natural genetic experiments and their influence on the metabolic capacities of the human body. By sampling the natural metabolic and genetic variability that is present in the general population, mGWAS identified over 150 associations between genetic variants and variation in the metabolic composition of human body fluids. Many of these genetic variants were found to be located in enzyme or transporter coding genes, whose functions match the biochemical nature of the associated metabolites. Associations identified by mGWAS can reveal novel biochemical knowledge, such as the function of uncharacterized genes, the biochemical identity of small molecules, and the structure of entire biochemical pathways. Here we review findings of recent mGWAS and discuss concrete examples of how their results can be interpreted in a biochemical context. We describe online resources that are available for mining mGWAS results. In this context, we present two concepts that also find more general applications in the field of metabolomics: strengthening of associations by looking at ratios between metabolite pairs and reconstruction of metabolic pathways by Gaussian graphical modeling.
Subject(s)
Biochemistry/methods , Genome-Wide Association Study/methods , Metabolomics/methods , Data Mining , HumansABSTRACT
Adverse levels of lipoproteins are highly heritable and constitute risk factors for cardiovascular outcomes. Hitherto, genome-wide association studies revealed 95 lipid-associated loci. However, due to the small effect sizes of these associations large sample numbers (>100 000 samples) were needed. Here we show that analyzing more refined lipid phenotypes, namely lipoprotein subfractions, can increase the number of significantly associated loci compared with bulk high-density lipoprotein and low-density lipoprotein analysis in a study with identical sample numbers. Moreover, lipoprotein subfractions provide novel insight into the human lipid metabolism. We measured 15 lipoprotein subfractions (L1-L15) in 1791 samples using (1)H-NMR (nuclear magnetic resonance) spectroscopy. Using cluster analyses, we quantified inter-relationships among lipoprotein subfractions. Additionally, we analyzed associations with subfractions at known lipid loci. We identified five distinct groups of subfractions: one (L1) was only marginally captured by serum lipids and therefore extends our knowledge of lipoprotein biochemistry. During a lipid-tolerance test, L1 lost its special position. In the association analysis, we found that eight loci (LIPC, CETP, PLTP, FADS1-2-3, SORT1, GCKR, APOB, APOA1) were associated with the subfractions, whereas only four loci (CETP, SORT1, GCKR, APOA1) were associated with serum lipids. For LIPC, we observed a 10-fold increase in the variance explained by our regression models. In conclusion, NMR-based fine mapping of lipoprotein subfractions provides novel information on their biological nature and strengthens the associations with genetic loci. Future clinical studies are now needed to investigate their biomedical relevance.
Subject(s)
Fasting/physiology , Genetic Loci/genetics , Lipoproteins/analysis , Lipoproteins/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Body Mass Index , Chromosome Mapping , Delta-5 Fatty Acid Desaturase , Genetics, Population , Genome-Wide Association Study , Humans , Lipid Metabolism , Magnetic Resonance Spectroscopy , Male , Phenotype , Risk Factors , Young AdultABSTRACT
Prostate cancer is a dominant health concern calling for advanced diagnostic tools. Utilizing digital pathology and artificial intelligence, this study explores the potential of 11 deep neural network architectures for automated Gleason grading in prostate carcinoma focusing on comparing traditional and recent architectures. A standardized image classification pipeline, based on the AUCMEDI framework, facilitated robust evaluation using an in-house dataset consisting of 34,264 annotated tissue tiles. The results indicated varying sensitivity across architectures, with ConvNeXt demonstrating the strongest performance. Notably, newer architectures achieved superior performance, even though with challenges in differentiating closely related Gleason grades. The ConvNeXt model was capable of learning a balance between complexity and generalizability. Overall, this study lays the groundwork for enhanced Gleason grading systems, potentially improving diagnostic efficiency for prostate cancer.
Subject(s)
Deep Learning , Neoplasm Grading , Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/pathology , Neural Networks, Computer , Image Interpretation, Computer-Assisted/methodsABSTRACT
Metabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal.
Subject(s)
Metabolomics , Humans , Male , Adult , Metabolome , Exercise/physiology , Young AdultABSTRACT
Metabolic challenge protocols, such as the oral glucose tolerance test, can uncover early alterations in metabolism preceding chronic diseases. Nevertheless, most metabolomics data accessible today reflect the fasting state. To analyze the dynamics of the human metabolome in response to environmental stimuli, we submitted 15 young healthy male volunteers to a highly controlled 4 d challenge protocol, including 36 h fasting, oral glucose and lipid tests, liquid test meals, physical exercise, and cold stress. Blood, urine, exhaled air, and breath condensate samples were analyzed on up to 56 time points by MS- and NMR-based methods, yielding 275 metabolic traits with a focus on lipids and amino acids. Here, we show that physiological challenges increased interindividual variation even in phenotypically similar volunteers, revealing metabotypes not observable in baseline metabolite profiles; volunteer-specific metabolite concentrations were consistently reflected in various biofluids; and readouts from a systematic model of ß-oxidation (e.g., acetylcarnitine/palmitylcarnitine ratio) showed significant and stronger associations with physiological parameters (e.g., fat mass) than absolute metabolite concentrations, indicating that systematic models may aid in understanding individual challenge responses. Due to the multitude of analytical methods, challenges and sample types, our freely available metabolomics data set provides a unique reference for future metabolomics studies and for verification of systems biology models.
Subject(s)
Metabolomics , Stress, Physiological , Adult , Breath Tests , Carnitine/analogs & derivatives , Carnitine/metabolism , Cold Temperature , Exercise , Fasting/blood , Fasting/urine , Fatty Acids/metabolism , Glucose Tolerance Test , Humans , Lipid Metabolism/physiology , Lipids , Magnetic Resonance Spectroscopy , Male , Metabolome/physiology , Models, Biological , Oxidation-ReductionABSTRACT
BACKGROUND: The currently available immunotherapies already changed the strategy how many cancers are treated from first to last line. Understanding even the most complex heterogeneity in tumor tissue and mapping the spatial cartography of the tumor immunity allows the best and optimized selection of immune modulating agents to (re-)activate the patient's immune system and direct it against the individual cancer in the most effective way. RECENT FINDINGS: Primary cancer and metastases maintain a high degree of plasticity to escape any immune surveillance and continue to evolve depending on many intrinsic and extrinsic factors In the field of immune-oncology (IO) immune modulating agents are recognized as practice changing therapeutic modalities. Recent studies have shown that an optimal and lasting efficacy of IO therapeutics depends on the understanding of the spatial communication network and functional context of immune and cancer cells within the tumor microenvironment. Artificial intelligence (AI) provides an insight into the immune-cancer-network through the visualization of very complex tumor and immune interactions in cancer tissue specimens and allows the computer-assisted development and clinical validation of such digital biomarker. CONCLUSIONS: The successful implementation of AI-supported digital biomarker solutions guides the clinical selection of effective immune therapeutics based on the retrieval and visualization of spatial and contextual information from cancer tissue images and standardized data. As such, computational pathology (CP) turns into "precision pathology" delivering individual therapy response prediction. Precision Pathology does not only include digital and computational solutions but also high levels of standardized processes in the routine histopathology workflow and the use of mathematical tools to support clinical and diagnostic decisions as the basic principle of a "precision oncology".
Subject(s)
Artificial Intelligence , Neoplasms , Humans , Neoplasms/therapy , Medical Oncology , Biomarkers , Precision Medicine/methods , Tumor MicroenvironmentABSTRACT
The human metabolism constantly responds to stimuli such as food intake, fasting, exercise, and stress, triggering adaptive biochemical processes across multiple metabolic pathways. To understand the role of these processes and disruptions thereof in health and disease, detailed documentation of healthy metabolic responses is needed but still scarce on a time-resolved metabolome-wide level. Here, we present the HuMet Repository, a web-based resource for exploring dynamic metabolic responses to six physiological challenges (exercise, 36 h fasting, oral glucose and lipid loads, mixed meal, cold stress) in healthy subjects. For building this resource, we integrated existing and newly derived metabolomics data measured in blood, urine, and breath samples of 15 young healthy men at up to 56 time points during the six highly standardized challenge tests conducted over four days. The data comprise 1.1 million data points acquired on multiple platforms with temporal profiles of 2,656 metabolites from a broad range of biochemical pathways. By embedding the dataset into an interactive web application, we enable users to easily access, search, filter, analyze, and visualize the time-resolved metabolomic readouts and derived results. Users can put metabolites into their larger context by identifying metabolites with similar trajectories or by visualizing metabolites within holistic metabolic networks to pinpoint pathways of interest. In three showcases, we outline the value of the repository for gaining biological insights and generating hypotheses by analyzing the wash-out of dietary markers, the complementarity of metabolomics platforms in dynamic versus cross-sectional data, and similarities and differences in systemic metabolic responses across challenges. With its comprehensive collection of time-resolved metabolomics data, the HuMet Repository, freely accessible at https://humet.org/, is a reference for normal, healthy responses to metabolic challenges in young males. It will enable researchers with and without computational expertise, to flexibly query the data for their own research into the dynamics of human metabolism.
ABSTRACT
Food intake triggers extensive changes in the blood metabolome. The kinetics of these changes depend on meal composition and on intrinsic, health-related characteristics of each individual, making the assessment of changes in the postprandial metabolome an opportunity to assess someone's metabolic status. To enable the usage of dietary challenges as diagnostic tools, profound knowledge about changes that occur in the postprandial period in healthy individuals is needed. In this study, we characterize the time-resolved changes in plasma levels of 634 metabolites in response to an oral glucose tolerance test (OGTT), an oral lipid tolerance test (OLTT), and a mixed meal (SLD) in healthy young males (n = 15). Metabolite levels for samples taken at different time points (20 per individual) during the challenges were available from targeted (132 metabolites) and non-targeted (502 metabolites) metabolomics. Almost half of the profiled metabolites (n = 308) showed a significant change in at least one challenge, thereof 111 metabolites responded exclusively to one particular challenge. Examples include azelate, which is linked to ω-oxidation and increased only in OLTT, and a fibrinogen cleavage peptide that has been linked to a higher risk of cardiovascular events in diabetes patients and increased only in OGTT, making its postprandial dynamics a potential target for risk management. A pool of 89 metabolites changed their plasma levels during all three challenges and represents the core postprandial response to food intake regardless of macronutrient composition. We used fuzzy c-means clustering to group these metabolites into eight clusters based on commonalities of their dynamic response patterns, with each cluster following one of four primary response patterns: (i) "decrease-increase" (valley-like) with fatty acids and acylcarnitines indicating the suppression of lipolysis, (ii) "increase-decrease" (mountain-like) including a cluster of conjugated bile acids and the glucose/insulin cluster, (iii) "steady decrease" with metabolites reflecting a carryover from meals prior to the study, and (iv) "mixed" decreasing after the glucose challenge and increasing otherwise. Despite the small number of subjects, the diversity of the challenges and the wealth of metabolomic data make this study an important step toward the characterization of postprandial responses and the identification of markers of metabolic processes regulated by food intake.
ABSTRACT
Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
Subject(s)
Metabolism, Inborn Errors , Metabolome , Humans , Metabolome/genetics , Metabolomics , Plasma/metabolism , Phenotype , Metabolism, Inborn Errors/genetics , Membrane Proteins/metabolism , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolismABSTRACT
Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses.