| 1. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 2. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 3. |
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| 4. |
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| 5. |
- Koivula, Robert W., et al.
(författare)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 6. |
- Koivula, Robert W., et al.
(författare)
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The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes : an IMI DIRECT study
- 2020
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Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 63:4, s. 744-756
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). Methods: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. Results: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. Conclusions/interpretation: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.
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| 7. |
- Mann, G. W., et al.
(författare)
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Intercomparison and evaluation of global aerosol microphysical properties among AeroCom models of a range of complexity
- 2014
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 14:9, s. 4679-4713
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Tidskriftsartikel (refereegranskat)abstract
- Many of the next generation of global climate models will include aerosol schemes which explicitly simulate the microphysical processes that determine the particle size distribution. These models enable aerosol optical properties and cloud condensation nuclei (CCN) concentrations to be determined by fundamental aerosol processes, which should lead to a more physically based simulation of aerosol direct and indirect radiative forcings. This study examines the global variation in particle size distribution simulated by 12 global aerosol microphysics models to quantify model diversity and to identify any common biases against observations. Evaluation against size distribution measurements from a new European network of aerosol supersites shows that the mean model agrees quite well with the observations at many sites on the annual mean, but there are some seasonal biases common to many sites. In particular, at many of these European sites, the accumulation mode number concentration is biased low during winter and Aitken mode concentrations tend to be overestimated in winter and underestimated in summer. At high northern latitudes, the models strongly underpredict Aitken and accumulation particle concentrations compared to the measurements, consistent with previous studies that have highlighted the poor performance of global aerosol models in the Arctic. In the marine boundary layer, the models capture the observed meridional variation in the size distribution, which is dominated by the Aitken mode at high latitudes, with an increasing concentration of accumulation particles with decreasing latitude. Considering vertical profiles, the models reproduce the observed peak in total particle concentrations in the upper troposphere due to new particle formation, although modelled peak concentrations tend to be biased high over Europe. Overall, the multimodel-mean data set simulates the global variation of the particle size distribution with a good degree of skill, suggesting that most of the individual global aerosol microphysics models are performing well, although the large model diversity indicates that some models are in poor agreement with the observations. Further work is required to better constrain size-resolved primary and secondary particle number sources, and an improved understanding of nucleation and growth (e. g. the role of nitrate and secondary organics) will improve the fidelity of simulated particle size distributions.
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| 8. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 9. |
- Andersson, C., et al.
(författare)
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MATCH-SALSA - Multi-scale Atmospheric Transport and CHemistry model coupled to the SALSA aerosol microphysics model - Part 1: Model description and evaluation
- 2015
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 8:2, s. 171-189
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Tidskriftsartikel (refereegranskat)abstract
- © Author(s) 2015. We have implemented the sectional aerosol dynamics model SALSA (Sectional Aerosol module for Large Scale Applications) in the European-scale chemistry-transport model MATCH (Multi-scale Atmospheric Transport and Chemistry). The new model is called MATCH-SALSA. It includes aerosol microphysics, with several formulations for nucleation, wet scavenging and condensation. The model reproduces observed higher particle number concentration (PNC) in central Europe and lower concentrations in remote regions. The modeled PNC size distribution peak occurs at the same or smaller particle size as the observed peak at four measurement sites spread across Europe. Total PNC is underestimated at northern and central European sites and accumulation-mode PNC is underestimated at all investigated sites. The low nucleation rate coefficient used in this study is an important reason for the underestimation. On the other hand, the model performs well for particle mass (including secondary inorganic aerosol components), while elemental and organic carbon concentrations are underestimated at many of the sites. Further development is needed, primarily for treatment of secondary organic aerosol, in terms of biogenic emissions and chemical transformation. Updating the biogenic secondary organic aerosol (SOA) scheme will likely have a large impact on modeled PM2.5 and also affect the model performance for PNC through impacts on nucleation and condensation.
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| 10. |
- Andersson, U, et al.
(författare)
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High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes
- 2000
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 192:4, s. 565-570
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Tidskriftsartikel (refereegranskat)abstract
- Lipopolysaccharide (LPS) is lethal to animals because it activates cytokine release, causing septic shock and tissue injury. Early proinflammatory cytokines (e.g., tumor necrosis factor [TNF] and interleukin [IL]-1) released within the first few hours of endotoxemia stimulate mediator cascades that persist for days and can lead to death. High mobility group 1 protein (HMG-1), a ubiquitous DNA-binding protein, was recently identified as a “late” mediator of endotoxin lethality. Anti–HMG-1 antibodies neutralized the delayed increase in serum HMG-1, and protected against endotoxin lethality, even when passive immunization was delayed until after the early cytokine response. Here we examined whether HMG-1 might stimulate cytokine synthesis in human peripheral blood mononuclear cell cultures. Addition of purified recombinant HMG-1 to human monocyte cultures significantly stimulated the release of TNF, IL-1α, IL-1β, IL-1RA, IL-6, IL-8, macrophage inflammatory protein (MIP)-1α, and MIP-1β; but not IL-10 or IL-12. HMG-1 concentrations that activated monocytes were within the pathological range previously observed in endotoxemic animals, and in serum obtained from septic patients. HMG-1 failed to stimulate cytokine release in lymphocytes, indicating that cellular stimulation was specific. Cytokine release after HMG-1 stimulation was delayed and biphasic compared with LPS stimulation. Computer-assisted image analysis demonstrated that peak intensity of HMG-1–induced cellular TNF staining was comparable to that observed after maximal stimulation with LPS. Administration of HMG-1 to Balb/c mice significantly increased serum TNF levels in vivo. Together, these results indicate that, like other cytokine mediators of endotoxin lethality (e.g., TNF and IL-1), extracellular HMG-1 is a regulator of monocyte proinflammatory cytokine synthesis.
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