| 1. |
- Bahls, M., et al.
(författare)
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Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium
- 2020
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 27:3
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints. © The European Society of Cardiology 2019.
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| 2. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 3. |
- Jugan, Juliann, et al.
(författare)
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The associations between p,p'-DDE levels and plasma levels of lipoproteins and their subclasses in an elderly population determined by analysis of lipoprotein content
- 2020
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Ingår i: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lipoproteins at aberrant levels are known to play a role in cardiovascular disease. The metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), physically associates with lipids and accumulates in adipose tissue. Little is known about which lipoproteins associate with p,p'-DDE. An association between p,p'-DDE exposure and altered levels of circulating lipids was assessed in a large human cohort using a detailed analysis of lipoprotein content.METHODS: Plasma samples were collected from the subset of 75-year old Swedes in the Prospective Investigation of the Vasculature of Uppsala Seniors (PIVUS) cohort who were not prescribed lipid lowering medication (n = 571). p,p'-DDE concentrations in plasma were measured using high-throughput solid phase extraction and gas chromatography-high resolution mass spectrometry. Analysis of plasma lipoprotein content was performed with nuclear magnetic resonance spectroscopy.RESULTS: Detectable levels of p,p'-DDE were found in the plasma samples of all subjects. Elevated p,p'-DDE levels were associated with increased concentrations of lipoproteins of all diameters, with the exception of high density lipoprotein (HDL) of diameters between 14.3 nm-10.9 nm. Of the lipoprotein constituents, triglycerides were most uniformly associated with elevated p,p'-DDE across lipoproteins. p,p'-DDE was furthermore associated with apolipoprotein B, but not apolipoprotein A1.CONCLUSIONS: The positive associations observed between each lipoprotein class and elevated p,p'-DDE support previous data suggesting that p,p'-DDE interacts with lipoproteins within plasma. It is speculated that both physio-chemical and biological mechanisms may explain why p,p'-DDE does not uniformly associate with lipids across lipoproteins.
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| 4. |
- Krishnaraja, Abinaya, et al.
(författare)
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Tuning of Source Material for InAs/InGaAsSb/GaSb Application-Specific Vertical Nanowire Tunnel FETs
- 2020
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Ingår i: ACS Applied Electronic Materials. - : American Chemical Society (ACS). - 2637-6113. ; 2:9, s. 2882-2887
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Tidskriftsartikel (refereegranskat)abstract
- Tunnel field-effect transistors (TFETs) are promising candidates that have demonstrated potential for and beyond the 3 nm technology node. One major challenge for the TFETs is to optimize the heterojunction for high drive currents while achieving steep switching. Thus far, such optimization has mainly been addressed theoretically. Here, we experimentally investigate the influence of the source segment composition on the performance for vertical nanowire InAs/InGaAsSb/GaSb TFETs. Compositional analysis using transmission electron microscopy is combined with simulations to interpret the results from electrical characterization data. The results show that subthreshold swing (S) and transconductance (gm) decrease with increasing arsenic composition until the strain due to lattice mismatch increases them both. The role of indium concentration at the junction is also examined. This systematic optimization has rendered sub-40 mV/dec operating TFETs with a record transconductance efficiency gm/ID = 100 V-1, and it shows that different source materials are preferred for various applications.
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| 5. |
- Lee, Duk-Hee, et al.
(författare)
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Lipophilic Environmental Chemical Mixtures Released During Weight-Loss : The Need to Consider Dynamics
- 2020
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Ingår i: Bioessays. - : Wiley. - 0265-9247 .- 1521-1878. ; 42:6
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Tidskriftsartikel (refereegranskat)abstract
- Intentional weight loss can increase health risk in the long-term, despite short-term benefits, because human adipose tissue is widely contaminated with various lipophilic environmental contaminants, especially persistent organic pollutants (POPs). Recently, chronic exposure to low POPs has emerged as a new risk factor for common metabolic diseases and cardiovascular diseases. The amount of POPs released from adipocytes to the circulation increases during weight loss, thereby increasing POPs exposure of other critical organs. Possible harmful effects due to release of POPs during weight loss are opposite to those usually expected from losing weight. It is speculated that this tradeoff can explain recent puzzling findings on intensive weight loss. The presence of POPs in adipose tissue adds a challenge to weight management and an optimal strategy of weight management needs to consider both fat mass and dynamics of POPs.
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| 6. |
- Lind, Lars, et al.
(författare)
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Commonly used clinical chemistry tests as mortality predictors : Results from two large cohort studies
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The normal ranges for clinical chemistry tests are usually defined by cut-offs given by the distribution in healthy individuals. This approach does however not indicate if individuals outside the normal range are more prone to disease.METHODS: We studied the associations and risk prediction of 11 plasma and serum biomarkers with all-cause mortality in two population-based cohorts: a Swedish cohort (X69) initiated in 1969, and the UK Biobank (UKB) initiated in 2006-2010, with up to 48- and 9-years follow-up, respectively.RESULTS: In X69 and in UKB, 18,529 and 425,264 individuals were investigated, respectively. During the follow-up time, 14,475 deaths occurred in X69 and 17,116 in UKB. All evaluated tests were associated with mortality in X69 (P<0.0001, except bilirubin P<0.005). For calcium, blood urea nitrogen, bilirubin, hematocrit, uric acid, and iron, U-shaped associations were seen (P<0.0001). For leukocyte count, gamma-glutamyl transferase, alkaline phosphatases and lactate dehydrogenase, linear positive associations were seen, while for albumin the association was negative. Similar associations were seen in UKB. Addition of all biomarkers to a model with classical risk factors improved mortality prediction (delta C-statistics: +0.009 in X69 and +0.023 in UKB, P<0.00001 in both cohorts).CONCLUSIONS: Commonly used clinical chemistry tests were associated with all-cause mortality both in the medium- and long-term perspective, and improved mortality prediction beyond classical risk factors. Since both linear and U-shaped relationships were found, we propose to define the normal range of a clinical chemistry test based on its association with mortality, rather than from the distribution.
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| 7. |
- Lind, Lars, et al.
(författare)
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Comparison of four non-alcoholic fatty liver disease detection scores in a Caucasian population
- 2020
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Ingår i: World Journal of Hepatology. - : Baishideng Publishing Group Inc.. - 1948-5182. ; 12:4, s. 149-159
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is a common disorder, with an estimated prevalence ranging from 20% to 35% in the general population. Several scores based on easily measurable biochemical and clinical parameters, including the fatty liver index (FLI), hepatic steatosis index (HSI), lipid accumulation product (LAP), and NAFLD liver fat score (LFS), have been developed for the detection of NAFLD. However, comparative information regarding the efficacy of these scores for predicting NAFLD in population-based samples comprising normal and high-risk individuals is lacking.AIMTo evaluate four NAFLD detection scores in two samples with different NAFLD risks.METHODSNAFLD screening was performed in a population-based sample of 50-year-old individuals in Uppsala, Sweden [n = 310; Prospective investigation of obesity, energy and metabolism (POEM) study] and a high-risk population comprising patients with a body mass index > 25 kg/m2 and either high plasma triglycerides (≥ 1.7 mmol/L) or type 2 diabetes (n = 310; EFFECT studies). NAFLD was defined as liver fat > 5.5% using magnetic resonance imaging-proton density fat fraction. FLI, HSI, LAP, and NAFLD LFS were assessed. A logistic regression model was used to evaluate the effectiveness of the different scores.RESULTSThe prevalence of NAFLD was 23% in POEM. FLI showed the highest receiver operating characteristic area under the curve (ROC AUC; 0.82) and was significantly better than the LAP score (P = 0.005 vs LAP, P = 0.08 vs LFS, P = 0.12 vs HSI) for detection of NAFLD. The other three indices performed equally in POEM (0.77-0.78). The prevalence of NAFLD was 74% in EFFECT; LFS performed best (ROC AUC 0.80) in this sample. The ROC AUC for LFS (0.80) was significantly higher than that for FLI (P = 0.0019) and LAP (P = 0.0022), but not HSI (P = 0.11). We performed a sensitivity analysis with stratification for the two high-risk subgroups (patients with diabetes or hypertriglyceridemia) from the EFFECT studies. LAP performed best in patients with hypertriglyceridemia. No major differences were observed between the other scores.CONCLUSIONThe four investigated NAFLD scores performed differently in the populationbased vs high-risk setting. FLI was preferable in the population-based setting, while LFS performed best in the high-risk setting.
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| 8. |
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| 9. |
- Salihovic, Samira, Associate Senior Lecturer, 1985-, et al.
(författare)
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Plasma perfluoroalkyls are associated with decreased levels of proteomic inflammatory markers in a cross-sectional study of an elderly population
- 2020
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 145
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Tidskriftsartikel (refereegranskat)abstract
- Perfluoroalkyl substances (PFAS) have been linked to immunotoxicity in experimental studies. Although PFAS exposure is associated with altered immune response in epidemiological studies of children, it is less known whether this is observed also in elderly adults. Eight PFAS and 86 proteins were measured in plasma from 965 elderly individuals from Sweden (all aged 70, 50% women). PFAS were measured using isotope-dilution ultra-pressure liquid chromatography coupled to tandem mass spectrometry. Proteins were measured using a multiplex proximity extension assay (PEA) and covered among others inflammatory marker proteins such as monocyte chemoattractant proteins, tumor necrosis factors, and interleukins. We examined cross-sectional associations using multivariable linear regression at two levels of adjustment. We observed significant decreases in levels of 24 proteins in relation to a ln-unit increase in PFAS concentrations following adjustment for sex, sample storage time in freezer, and correction for multiple testing. Associations of PFAS and hepatocyte growth factor (HGF) and macrophage colony-stimulating factor 1 (CSF-1) remained significant (p-value < 0.05) following full covariate adjustment for smoking, exercise habits, education, energy, and alcohol intake, body mass index (BMI), glomular filtration rate (GFR) as well as corticoid- and COX-inhibitor treatment. CSF-1 was inversely associated with perfluorohexane sulfonic acid (PFHxS) beta: -0.08: 95% confidence interval (CI); -0.13, -0.02), perfluorooctanoic acid (PFOA) beta: -0.04: 95% CI; -0.07, -0.006, perfluorononanoic acid (PFNA) beta: -0.04: 95% CI; -0.08, -0.003, perfluorodecanoic acid (PFDA) beta: -0.03: 95% CI; -0.06, -0.003, and perfluoroundecanoic acid (PFUnDA) beta: -0.05: 95% CI; -0.08, -0.02. The magnitude and direction of PFAS vs protein relationships were similar also for HGF. Our findings implicate PFAS exposure with decreased levels of proteomic markers of inflammation in elderly humans.
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| 10. |
- Shah, S, et al.
(författare)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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