| 21. |
- Folkersen, Lasse, et al.
(author)
-
Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
-
In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
-
Journal article (peer-reviewed)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.
|
|
| 22. |
- Folkersen, Lasse, et al.
(author)
-
Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
- 2017
-
In: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
-
Journal article (peer-reviewed)abstract
- Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
|
|
| 23. |
- Gustafsson, Stefan, et al.
(author)
-
Adiponectin and cardiac geometry and function in elderly : results from two community-based cohort studies
- 2010
-
In: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 162:3, s. 543-550
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Several smaller studies have indicated that adiponectin might be associated with left ventricular (LV) mass and function, but community-based studies with adequate sample size and adjustment for potential confounders are lacking. Our objective was to investigate such associations in two large community-based studies of elderly. DESIGN: Cross-sectional. METHODS: We evaluated cross-sectional relations between serum adiponectin and echocardiographic measures of cardiac geometry and function (LV mass index, LV relative wall thickness, LV end-diastolic diameter, left atrial diameter, ejection fraction, LV isovolumic relaxation time, and E/A ratio) in 954 70-year-old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), and in 427 71-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM). RESULTS: In models adjusted for age, sex, body mass index, systolic blood pressure, antihypertensive treatment, antidiabetic treatment, lipid-lowering medication, fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol, creatinine, and smoking, adiponectin was inversely associated with ejection fraction in men (beta, -1.62; 95% confidence interval (CI), -2.50, -0.75 in PIVUS; beta, -1.35; 95% CI, -2.41, -0.29 in ULSAM), but not in women. After additional adjustment for N-terminal pro-brain natriuretic peptide (NT-proBNP), the association between adiponectin and ejection fraction was attenuated (beta, -0.98; 95% CI, -1.86, -0.10 in PIVUS; beta, -0.75; 95% CI, -1.84, 0.35 in ULSAM). CONCLUSIONS: Serum adiponectin concentrations were associated with ejection fraction in men, and these associations were partially attenuated by NT-proBNP. Our results imply that adiponectin may be associated with systolic function through pathways that involve natriuretic peptides.
|
|
| 24. |
- Gustafsson, Stefan, et al.
(author)
-
Associations of circulating adiponectin with measures of vascular function and morphology
- 2010
-
In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:6, s. 2927-2934
-
Journal article (peer-reviewed)abstract
- CONTEXT: Some previous studies have reported an association between circulating adiponectin and selected measures of vascular function and morphology, but most of these studies have been performed in small samples of patients with preexisting disease. OBJECTIVE: We aimed to evaluate associations between circulating adiponectin and comprehensive measures of vascular function and morphology in a large sample of individuals from the community. DESIGN, SETTINGS, AND PARTICIPANTS: We conducted a cross-sectional investigation of 981 70-yr-old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). MAIN OUTCOME MEASURES: Measures of outcome included vascular function [common carotid artery (CCA) distensibility, flow-mediated dilation, endothelium-dependent and endothelium-independent vasodilation using invasive methods] and vascular morphology [intima-media (IM) thickness, plaque presence, gray scale median (GSM) in the IM and plaques]. RESULTS: In age- and sex-adjusted models, adiponectin was positively associated with IM-GSM, plaque GSM, CCA distensibility, endothelium-dependent and endothelium-independent vasodilation. In multivariable models (with additional adjustment for body mass index; systolic blood pressure; antihypertensive, antidiabetic, and lipid-lowering medication; fasting blood glucose; total cholesterol; high-density lipoprotein cholesterol; creatinine; and smoking), adiponectin remained positively associated with IM-GSM [beta = 2.06; 95% confidence interval (CI), 0.54, 3.58], plaque GSM (beta = 3.11; 95% CI, 0.36, 5.86), and CCA distensibility (beta = 0.04; 95% CI, 0.00, 0.07). CONCLUSIONS: Serum levels of adiponectin were positively associated with IM-GSM and plaque GSM (indicating lower fat content in the IM and plaques) and CCA distensibility (indicating higher wall elasticity), independent of potential confounders. Our results imply that adiponectin is associated with less arterial pathology.
|
|
| 25. |
- Gustafsson, Stefan, et al.
(author)
-
Electromagnetic dispersion modeling and measurements for HVDC power cables
- 2014
-
In: IEEE Transactions on Power Delivery. - : IEEE Press. - 0885-8977 .- 1937-4208. ; 29:6, s. 2439-2447
-
Journal article (peer-reviewed)abstract
- This paper provides a general framework for electromagnetic (EM) modeling, sensitivity analysis, computation, and measurements regarding the wave propagation characteristics of high-voltage direct-current (HVDC) power cables. The modeling is motivated by the potential use with transient analysis, partial-discharge measurements, fault localization and monitoring, and is focused on very long (10 km or more) HVDC power cables with transients propagating in the low-frequency regime of about 0-100 kHz. An exact dispersion relation is formulated together with a discussion on practical aspects regarding the computation of the propagation constant. Experimental time-domain measurement data from an 80-km-long HVDC power cable are used to validate the electromagnetic model, and a mismatch calibration procedure is devised to account for the connection between the measurement equipment and the cable. Quantitative sensitivity analysis is devised to study the impact of parameter uncertainty on wave propagation characteristics. The sensitivity analysis can be used to study how material choices affect the propagation characteristics, and to indicate which material parameters need to be identified accurately in order to achieve accurate fault localization. The analysis shows that the sensitivity of the propagation constant due to a change in the conductivity in the three metallic layers (the inner conductor, the intermediate lead shield, and the outer steel armor) is comparable to the sensitivity with respect to the permittivity of the insulating layer. Hence, proper modeling of the EM fields inside the metallic layers is crucial in the low-frequency regime of 0-100 kHz.
|
|
| 26. |
- Gustafsson, Stefan, et al.
(author)
-
Oxidative Stress and Inflammatory Markers in Relation to Circulating Levels of Adiponectin
- 2013
-
In: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 21:7, s. 1467-1473
-
Journal article (peer-reviewed)abstract
- Objective: Previous epidemiological studies together with animal studies have suggested an association between adiponectin and oxidative stress and inflammation, but community-based studies are lacking. Our objective was to investigate the relative importance of oxidative stress and inflammatory markers, representing different pathways in relation to adiponectin. Design and Methods: In a cross-sectional sample of 929 70-year-old individuals (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors study, relations between serum adiponectin and oxidative stress [conjugated dienes (CD), homocysteine, total antioxidant capacity, oxidized low-density lipoprotein (OxLDL), OxLDL antibodies, baseline CD of LDL, glutathione (GSH), total glutathione (TGSH), glutathione disulfide], circulation interleukins (IL-6, IL-8), other cytokines [tumor necrosis factor alpha, monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), vascular endothelial growth factor], cell adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, P-selectin, L-selectin), and systemic inflammatory markers [C-reactive protein (CRP), leukocyte count] in separate models were investigated. Results: In age- and sex-adjusted, as well as multivariable-adjusted models, adiponectin was significantly and positively associated with GSH, log TGSH, whereas an inverse association was observed for CD and log EGF. An inverse association between adiponectin and MCP-1, log E-selectin, and log CRP was significant in age- and sex-adjusted models, but not in multivariable-adjusted models. Conclusions: Our results imply that higher levels of adiponectin are associated with a more beneficial oxidative stress profile, with higher levels of principal anti-oxidative GSH and total GSH together with lower levels of lipid peroxidation, possibly through shared pathways. Further studies are needed to investigate whether changes in the oxidative stress profile may be a mechanism linking adiponectin with type 2 diabetes and/or cardiovascular disease.
|
|
| 27. |
|
|
| 28. |
- Kanoni, Stavroula, et al.
(author)
-
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
-
In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
-
Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
|
|
| 29. |
- King, Carina, et al.
(author)
-
COVID-19—a very visible pandemic
- 2020
-
In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 396:10248, s. 15-15
-
Journal article (peer-reviewed)
|
|
| 30. |
- Klaric, Lucija, et al.
(author)
-
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
-
In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
-
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.
|
|
