| 1. |
- Klaric, Lucija, et al.
(författare)
-
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
-
Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
-
Annan publikation (övrigt vetenskapligt/konstnärligt)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.
|
|
| 2. |
|
|
| 3. |
- Hagstrom, Emil, et al.
(författare)
-
IMPACT OF BODY WEIGHT AT AGE 20 AND WEIGHT GAIN DURING ADULTHOOD ON MIDLIFE CORONARY ARTERY CALCIUM IN 15,000 MEN AND WOMEN : AN INTERIM ANALYSIS OF THE SWEDISH CARDIOPULMONARY BIOIMAGE STUDY
- 2019
-
Ingår i: Journal of the American College of Cardiology. - : ELSEVIER SCIENCE INC. - 0735-1097 .- 1558-3597. ; 73:9, s. 1692-1692
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundElevated body weight in adolescence is strongly associated with early cardiovascular disease, but whether this association is traceable to weight in early adulthood, or to weight gain with subsequent high adult weight is not known. Using data from the Swedish CArdioPulmonary bioImage Study (SCAPIS), we investigated the association between weight at age 20, weight gain to midlife and coronary artery calcium score (CACS) at midlife.MethodsIn the first 15,810 participants in SCAPIS (mean age 58 years, 52% women), data on CACS at midlife, self-reported body weight at age 20 and weight at examination in SCAPIS were recorded.ResultsCACS in midlife was significantly higher with increasing weight at age 20 (p<0.001 for both sexes), and then increased with weight gain until midlife at all levels of body weight at age 20 after adjusting for age, height, smoking, alcohol intake, education level, exercise levels and LDL cholesterol. However, the association with weight gain was only significant in men (p = 0.047), not in women (p=0.474). No significant interaction was seen between weight at age 20 and midlife weight with CACS. The effect of weight at age 20 on CACS was significantly more marked in men than in women, as was the effect of weight gain (p<0.001 for both interactions).ConclusionWeight at age 20 and weight gain to midlife were both related to CACS, but much more markedly so in men than in women, indicating a generally larger effect of both early adult weight and further weight gain until midlife on CACS in men, compared to women.
|
|
| 4. |
- Lindholm, Daniel, 1982-
(författare)
-
Platelet Inhibition, Revascularization, and Risk Prediction in Non-ST-elevation Acute Coronary Syndromes
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease is the leading cause of death worldwide and ischemic heart disease is the most common manifestation. Despite improved outcomes during the last decades, patients with acute coronary syndromes (ACS) are still at substantial risk of recurrent ischemic events and mortality.The aims of this thesis were to investigate the effect of the novel antiplatelet agent ticagrelor versus clopidogrel in patients with non-ST-elevation ACS (NSTE-ACS), overall and in relation to initial revascularization, and to explore this effect in relation to cardiac biomarkers. The impact of timing of revascularization in non-ST-elevation myocardial infarction (NSTEMI) was also studied, by assessing risk of mortality and recurrent myocardial infarction in relation to delay of percutaneous coronary intervention (PCI) in a nation-wide cohort. Finally, a novel clinical prediction model based on angiographic findings, biomarkers, and clinical characteristics was developed to estimate risk of ischemic events after performed revascularization.Ticagrelor treatment compared with clopidogrel was associated with a reduction in the composite endpoint of cardiovascular death/myocardial infarction/stroke and mortality alone, without any increase in overall major bleeding, but increased non-CABG-related major bleeding. The effect of ticagrelor over clopidogrel was consistent independent of initial revascularization. Elevated high-sensitivity cardiac troponin-T predicted benefit of ticagrelor over clopidogrel, while no difference between treatments was detected at normal levels. In patients with NSTEMI, PCI treatment within two days after hospital admission was associated with lower risk of all-cause death and recurrent myocardial infarction compared with delayed PCI. The new clinical prediction model included the following variables: prior vascular disease, extent of coronary artery disease, level of N-terminal pro-B-type natriuretic peptide and estimated glomerular filtration rate; and showed good discriminatory ability for the risk prediction of cardiovascular death/myocardial infarction/stroke and cardiovascular death alone.In conclusion, these results show that ticagrelor reduces the risk of recurrent ischemic events and mortality in patients with NSTE-ACS when compared with clopidogrel, and this effect seems independent of performed revascularization. The results also indicate that biomarkers could be used to select patients who would benefit most from more intense platelet inhibition. Furthermore, early PCI in NSTEMI seems to be associated with improved outcome. Finally, the novel clinical prediction model based only on four variables showed good discriminatory ability, which makes it a potentially effective and simple tool for tailored treatment based on individual risk of recurrent events.
|
|
| 5. |
- Repetto, Linda, et al.
(författare)
-
Genetic mechanisms of 184 neuro-related proteins in human plasma.
- 2023
-
Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.
|
|
| 6. |
- Repetto, Linda, et al.
(författare)
-
Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.
- 2023
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
|
|
| 7. |
|
|
| 8. |
- Anderson, Christopher J., et al.
(författare)
-
Response to Comment on "Estimating the reproducibility of psychological science"
- 2016
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 351:6277
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Gilbert et al. conclude that evidence from the Open Science Collaboration's Reproducibility Project: Psychology indicates high reproducibility, given the study methodology. Their very optimistic assessment is limited by statistical misconceptions and by causal inferences from selectively interpreted, correlational data. Using the Reproducibility Project: Psychology data, both optimistic and pessimistic conclusions about reproducibility are possible, and neither are yet warranted.
|
|
| 9. |
- Andersson-Engels, Stefan, et al.
(författare)
-
Clinical fluorescence imaging
- 2008
-
Ingår i: Lasers in Medicine.
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
|
|
| 10. |
|
|
