| 1. |
- Fall, Tove, 1979-, et al.
(författare)
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Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:10, s. 2114-2124
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesisIdentification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction.MethodsIn this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies.ResultsOut of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes.Conclusions/interpretationWe found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes.Access to research materialsMetabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS).
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| 2. |
- Ganna, Andrea, et al.
(författare)
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Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease
- 2014
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:12, s. e1004801-
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
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| 3. |
- Ganna, Andrea, et al.
(författare)
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Large-scale non-targeted metabolomic profiling in three human population-based studies
- 2016
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Ingår i: Metabolomics. - : Springer Science and Business Media LLC. - 1573-3882 .- 1573-3890. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Non-targeted metabolomic profiling is used to simultaneously assess a large part of the metabolome in a biological sample. Here, we describe both the analytical and computational methods used to analyze a large UPLC–Q-TOF MS-based metabolomic profiling effort using plasma and serum samples from participants in three Swedish population-based studies of middle-aged and older human subjects: TwinGene, ULSAM and PIVUS. At present, more than 200 metabolites have been manually annotated in more than 3600 participants using an in-house library of standards and publically available spectral databases. Data available at the metabolights repository include individual raw unprocessed data, processed data, basic demographic variables and spectra of annotated metabolites. Additional phenotypical and genetic data is available upon request to cohort steering committees. These studies represent a unique resource to explore and evaluate how metabolic variability across individuals affects human diseases.
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| 4. |
- Lind, Lars, et al.
(författare)
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A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke
- 2020
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 29:2
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose:To search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach.Methods: We identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites.Results:In TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR.69 per SD change, 95% CI.57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively).Conclusions:An inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.
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| 5. |
- Nowak, Christoph, et al.
(författare)
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Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels : A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study
- 2016
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.
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| 6. |
- Nowak, Christoph, et al.
(författare)
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Glucose challenge metabolomics implicates medium-chain acylcarnitines in insulin resistance
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance (IR) predisposes to type 2 diabetes and cardiovascular disease but its causes are incompletely understood. Metabolic challenges like the oral glucose tolerance test (OGTT) can reveal pathogenic mechanisms. We aimed to discover associations of IR with metabolite trajectories during OGTT. In 470 non-diabetic men (age 70.6 +/- 0.6 years), plasma samples obtained at 0, 30 and 120 minutes during an OGTT were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. IR was assessed with the hyperinsulinemic-euglycemic clamp method. We applied age-adjusted linear regression to identify metabolites whose concentration change was related to IR. Nine trajectories, including monounsaturated fatty acids, lysophosphatidylethanolamines and a bile acid, were significantly associated with IR, with the strongest associations observed for medium-chain acylcarnitines C10 and C12, and no associations with L-carnitine or C2-, C8-, C14- or C16-carnitine. Concentrations of C10-and C12-carnitine decreased during OGTT with a blunted decline in participants with worse insulin resistance. Associations persisted after adjustment for obesity, fasting insulin and fasting glucose. In mouse 3T3-L1 adipocytes exposed to different acylcarnitines, we observed blunted insulin-stimulated glucose uptake after treatment with C10-or C12-carnitine. In conclusion, our results identify medium-chain acylcarnitines as possible contributors to IR.
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| 7. |
- Nowak, Christoph, et al.
(författare)
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Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.
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| 8. |
- Salihovic, Samira, 1985-, et al.
(författare)
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Identification of metabolic profiles associated with human exposure to perfluoroalkyl substances
- 2019
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Ingår i: Journal of Exposure Science and Environmental Epidemiology. - : Nature Publishing Group. - 1559-0631 .- 1559-064X. ; 29:2, s. 196-205
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Tidskriftsartikel (refereegranskat)abstract
- Recent epidemiological studies suggest that human exposure to perfluoroalkyl substances (PFASs) may be associated with type 2 diabetes and other metabolic phenotypes. To gain further insights regarding PFASs exposure in humans, we here aimed to characterize the associations between different PFASs and the metabolome. In this cross-sectional study, we investigated 965 individuals from Sweden (all aged 70 years, 50% women) sampled in 2001-2004. PFASs were analyzed in plasma using isotope-dilution ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Non-target metabolomics profiling was performed in plasma using UPLC coupled to time-of-flight mass spectrometry (UPLC-QTOFMS) operated in positive electrospray mode. Multivariate linear regression analysis was used to investigate associations between circulating levels of PFASs and metabolites. In total, 15 metabolites, predominantly from lipid pathways, were associated with levels of PFASs following adjustment for sex, smoking, exercise habits, education, energy, and alcohol intake, after correction for multiple testing. Perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUnDA) were strongly associated with multiple glycerophosphocholines and fatty acids including docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). We also found that the different PFASs evaluated were associated with distinctive metabolic profiles, suggesting potentially different biochemical pathways in humans.
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| 9. |
- Salihovic, Samira, Associate Senior Lecturer, 1985-, et al.
(författare)
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Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Better risk prediction and new molecular targets are key priorities in type 2 diabetes (T2D) research. Little is known about the role of the urine metabolome in predicting the risk of T2D. We aimed to use non-targeted urine metabolomics to discover biomarkers and improve risk prediction for T2D. Urine samples from two community cohorts of 1,424 adults were analyzed by ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). In a discovery/replication design, three out of 62 annotated metabolites were associated with prevalent T2D, notably lower urine levels of 3-hydroxyundecanoyl-carnitine. In participants without diabetes at baseline, LASSO regression in the training set selected six metabolites that improved prediction of T2D beyond established risk factors risk over up to 12 years' follow-up in the test sample, from C-statistic 0.866 to 0.892. Our results in one of the largest non-targeted urinary metabolomics study to date demonstrate the role of the urine metabolome in identifying at-risk persons for T2D and suggest urine 3-hydroxyundecanoyl-carnitine as a biomarker candidate.
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| 10. |
- Salihovic, Samira, 1985-, et al.
(författare)
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The metabolic fingerprint of p,p'-DDE and HCB exposure in humans
- 2016
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Ingår i: Environment International. - Oxford, United Kingdom : Elsevier. - 0160-4120 .- 1873-6750. ; 88, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) are organochlorine pesticides with well-known endocrine disrupting properties. Exposure to p,p'-DDE and HCB concerns human populations worldwide and has been linked to metabolic disorders such as obesity and type 2 diabetes, but details about these associations in humans from the general population are largely unknown.Objectives: We investigated the associations between p,p'-DDE and HCB exposure and global metabolomic profiles in serum samples from 1016 participants from the Swedish population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.Methods: HCB and p,p'-DDE levels were determined using gas chromatography coupled to high-resolution mass spectrometry (GC-HRMS). Metabolite levels were determined by using a non-targeted metabolomics approach with ultra-performance liquid chromatography coupled to time-of- flight mass spectrometry (UPLC-TOFMS). Association analyses were performed using multivariate linear regression.Results: We found circulating levels of p,p-DDE and HCB to be significantly associated with circulating levels of 16 metabolites following adjustment for age, sex, education level, exercise habits, smoking, energy intake, and alcohol intake. The majority of the 16 metabolites belong to lipid metabolism pathways and include fatty acids, glycerophospholipids, sphingolipids, and glycerolipids. Overall, p,p'-DDE and HCB levels were found to be correlated to different metabolites, which suggests that different metabolic fingerprints may be related to circulating levels of these two pesticides.Conclusions: Our findings establish a link between human exposure to organochlorine pesticides and metabolites of key metabolic processes mainly related to human lipid metabolism.
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