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- Klaric, Lucija, et al.
(author)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Other publication (other academic/artistic)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 2. |
- Espregueira Themudo, Raquel, 1978-, et al.
(author)
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Clinically unrecognized myocardial scars detected by MR are not associated with coronary artery disease
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Other publication (other academic/artistic)abstract
- Background: We have previously discovered an unexpected high prevalence of unrecognized myocardial infarction (UMI) scars by delayed-enhanced magnetic resonance imaging (DE-MRI) in the general elderly population. We now investigated if those UMIs were associated with coronary artery disease (CAD). Methods: Eighty-eight subjects from the PIVUS study (age 75-years) who had been investigated with DE-MRI (45 with UMI and 43 without DE-MRI-detected scars) underwent coronary computed tomography angiography (CTA) to assess Agatston calcium score and coronary artery stenosis. Of those, 65 also performed an exercise ECG test. Results: No differences were found between the subjects with UMI and the group without DE-MRI-detected scars regarding the number of coronary artery segments with significant stenosis, Agatston calcium score, or degree of ST-depression at the exercise test. Conclusion: DE-MRI-detected UMI scars do not have an increased prevalence of coronary artery stenosis or signs of myocardial ischemia at exercise test when compared to a control group. These findings indicate that UMI scars in general are not related to CAD.
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| 3. |
- Nowak, Christoph, et al.
(author)
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Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
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Other publication (other academic/artistic)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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| 5. |
- Diamanti, Klev, 1987-, et al.
(author)
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Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissues
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Other publication (other academic/artistic)abstract
- Background: Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific alterations is challenging and requires a multi-omics approach. In this study, we aimed at discovering associations of metabolites from subcutaneous adipose tissue (SAT) and plasma with the volume, the fat fraction (FF) and the insulin sensitivity (Ki) of specific tissues using [18F]FDG PET/MRI.Materials and Methods: In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body-mass-index (BMI) we calculated associations between parameters of whole-body FDG PET/MRI during clamp and non-targeted metabolomics profiling for SAT and blood plasma. We also used a rule-based classifier to identify a large collection of prevalent patterns of co-dependent metabolites that characterize non-diabetes (ND) and T2D.Results: The plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Ki in visceral adipose tissue (VAT) and SAT, was positively associated with several species of lysophospholipids while the opposite applied to branched-chain amino acids (BCAA) and their intermediates. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. On the contrary, bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Finally, we presented a transparent machine-learning model that predicted ND or T2D in “unseen” data with an accuracy of 78%.Conclusions: Novel associations of several metabolites from SAT and plasma with the FF, volume and insulin senstivity of various tissues throughout the body were discovered using PET/MRI and a new integrative multi-omics approach. A promising computational model that predicted ND and T2D with high certainty, suggested novel non-linear interdependencies of metabolites.
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| 8. |
- Lind, Lars, et al.
(author)
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High variability of the R-wave amplitude predicts incident heart failure in the elderly: a cohort study using machine learning
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Other publication (other academic/artistic)abstract
- Aims: Early identification of individuals at risk for heart failure (HF) may improve their poor prognosis. The aim was to test if a prediction model of ECG variables added to traditional risk factors could improve the prediction of incident HF versus traditional risk factors alone.Methods and Results: The PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (1016 individuals aged 70 years) was used for analysis of 23 ECG variables measured in 6 precordial leads. Out of 6 machine learning models used in a training dataset, the one with the best accuracy was used for the testing dataset. During 15 years of follow-up, 107 of 836 included individuals at risk were diagnosed with HF. Adding the 8 best ECG variables, identified by random forest in the training dataset, to traditional risk factors resulted in an improvement of the area under the ROC curve by 11.7% (p=0.0043) compared to the traditional risk factor model alone. A high beat-to-beat variation of the R amplitude (SD Ramp) in V1 was the most powerful predictive ECG variable. A decreased low Frequency/high frequency ratio, a heart rate variability index, was correlated to a high SD Ramp in V1 (p=0.002). Conclusion: Adding ECG variables to traditional cardiovascular risk factors were valuable for prediction of incident HF in an elderly population. The improvement in C statistics by adding the 8 identified ECG variables was quite substantial, which if reproduced in other populations, might be used as a screening tool for HF risk in clinical practice.
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| 10. |
- Snellman, Greta, 1978-, et al.
(author)
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Serum 25-hydroxyvitamin D in relation to BMD and fractures in a Swedish cohort of women and men
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Other publication (other academic/artistic)abstract
- Background/aimVitamin D insufficiency has been suggested to be common and to cause osteoporotic fractures. Results from previous studies are inconsistent. The aim of our study was to assess if circulating vitamin D is associated with incident fractures and bone mineral density (BMD) among elderly Swedish men and women.MethodA population-based cohort consisting of 1002 Swedish men and women, aged 70-years at baseline with a setting at latitude 60o north, was followed for 7 years. Serum vitamin D (25(OH)D) at baseline was analysed by an immunoassay. Fractures during follow-up were identified from registry data and BMD was measured with DXA. Association between 25(OH)D levels and time to fracture was our primary endpoint and BMD our secondary outcome.ResultMean S-25(OH)Dlevel was 58 (SD 20) nmol/L and 38% of the participants had levels <50 nmol/L. After multivariable adjustment, S-25(OH)D was only associated with total body BMD among men (P=0.03) but the relation was weak. Each SD increase in S-25(OH)D (approximately 20 nmol/L) conferred a 1% increase in total body BMD. Low vitamin D levels were not associated with lower BMD at the total hip or the lumbar spine in men or women. During follow-up, 155 (15%) of the participants sustained a fracture. No association between 25(OH)D and the rate of fracture was evident. The lowest quintile compared to highest quintile of 25(OH)D conferred a HR of 1.13 (95% CI 0.65-1.94).ConclusionIn a general population of elderly Swedish men and women, serum vitamin D is not a strong determinant of fractures or of low bone mineral density.
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