| 31. |
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| 32. |
- Drake, Isabel, et al.
(författare)
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Methodological considerations for identifying multiple plasma proteins associated with all-cause mortality in a population-based prospective cohort
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Novel methods to characterize the plasma proteome has made it possible to examine a wide range of proteins in large longitudinal cohort studies, but the complexity of the human proteome makes it difficult to identify robust protein-disease associations. Nevertheless, identification of individuals at high risk of early mortality is a central issue in clinical decision making and novel biomarkers may be useful to improve risk stratification. With adjustment for established risk factors, we examined the associations between 138 plasma proteins measured using two proximity extension assays and long-term risk of all-cause mortality in 3,918 participants of the population-based Malmö Diet and Cancer Study. To examine the reproducibility of protein-mortality associations we used a two-step random-split approach to simulate a discovery and replication cohort and conducted analyses using four different methods: Cox regression, stepwise Cox regression, Lasso-Cox regression, and random survival forest (RSF). In the total study population, we identified eight proteins that associated with all-cause mortality after adjustment for established risk factors and with Bonferroni correction for multiple testing. In the two-step analyses, the number of proteins selected for model inclusion in both random samples ranged from 6 to 21 depending on the method used. However, only three proteins were consistently included in both samples across all four methods (growth/differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide, and epididymal secretory protein E4). Using the total study population, the C-statistic for a model including established risk factors was 0.7222 and increased to 0.7284 with inclusion of the most predictive protein (GDF-15; P < 0.0001). All multiple protein models showed additional improvement in the C-statistic compared to the single protein model (all P < 0.0001). We identified several plasma proteins associated with increased risk of all-cause mortality independently of established risk factors. Further investigation into the putatively causal role of these proteins for longevity is needed. In addition, the examined methods for identifying multiple proteins showed tendencies for overfitting by including several putatively false positive findings. Thus, the reproducibility of findings using such approaches may be limited.
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| 33. |
- Edsfeldt, Andreas, et al.
(författare)
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Impaired Fibrous Repair: A Possible Contributor to Atherosclerotic Plaque Vulnerability in Patients With Type II Diabetes.
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 34:9, s. 2143-2150
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes mellitus (DM) type II is increasing rapidly worldwide. Patients with DM II have a greater atherosclerotic burden and higher risk of developing cardiovascular complications. Inflammation has been proposed as the main cause for the high risk of atherosclerotic disease in DM II. In this study, we compared markers of inflammation and fibrous repair in plaques from subjects with and without DM II.
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| 34. |
- Edsfeldt, Andreas, et al.
(författare)
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Proinflammatory Role of Sphingolipids and Glycosphingolipids in the Human Atherosclerotic Plaque
- 2016
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 36:6, s. 1132-1140
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Lipids are central to the development of atherosclerotic plaques. Specifically, which lipids are culprits remains controversial, and promising targets have failed in clinical studies. Sphingolipids are bioactive lipids present in atherosclerotic plaques, and they have been suggested to have both proatherogenic and antiatherogenic. However, the biological effects of these lipids remain unknown in the human atherosclerotic plaque. The aim of this study was to assess plaque levels of sphingolipids and investigate their potential association with and contribution to plaque vulnerability.APPROACH AND RESULTS: Glucosylceramide, lactosylceramide, ceramide, dihydroceramide, sphingomyelin, and sphingosine-1-phosphate were analyzed in homogenates from 200 human carotid plaques using mass spectrometry. Inflammatory activity was determined by analyzing plaque levels of cytokines and plaque histology. Caspase-3 was analyzed by ELISA technique. Expression of regulatory enzymes was analyzed with RNA sequencing. Human coronary artery smooth muscle cells were used to analyze the potential role of the 6 sphingolipids as inducers of plaque inflammation and cellular apoptosis in vitro. All sphingolipids were increased in plaques associated with symptoms and correlated with inflammatory cytokines. All sphingolipids, except sphingosine-1-phosphate, also correlated with histological markers of plaque instability. Lactosylceramide, ceramide, sphingomyelin, and sphingosine-1-phosphate correlated with caspase-3 activity. In vitro experiments revealed that glucosylceramide, lactosylceramide, and ceramide induced cellular apoptosis. All analyzed sphingolipids induced an inflammatory response in human coronary artery smooth muscle cells.CONCLUSIONS: This study shows for the first time that sphingolipids and particularly glucosylceramide are associated with and are possible inducers of plaque inflammation and instability, pointing to sphingolipid metabolic pathways as possible novel therapeutic targets.
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| 35. |
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| 36. |
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| 37. |
- Eicher, John D., et al.
(författare)
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Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:1, s. 40-55
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Tidskriftsartikel (refereegranskat)abstract
- Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
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| 38. |
- Enhörning, Sofia, et al.
(författare)
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Plasma copeptin and the risk of diabetes mellitus.
- 2010
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Ingår i: Circulation. - 1524-4539. ; 121:19, s. 51-2102
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Animal studies suggest that the arginine vasopressin system may play a role in glucose metabolism, but data from humans are limited. METHODS AND RESULTS: We analyzed plasma copeptin (copeptin), a stable C-terminal fragment of the arginine vasopressin prohormone. Using baseline and longitudinal data from a Swedish population-based sample (n=4742; mean age, 58 years; 60% women) and multivariable logistic regression, we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes mellitus at baseline, insulin resistance (top quartile of fasting plasma insulin among nondiabetic subjects), and incident diabetes mellitus on long-term follow-up. New-onset diabetes mellitus was ascertained through 3 national and regional registers. All models were adjusted for clinical and anthropometric risk factors, cystatin C, and C-reactive protein. In cross-sectional analyses, increasing copeptin was associated with prevalent diabetes mellitus (P=0.04) and insulin resistance (P<0.001). During 12.6 years of follow-up, 174 subjects (4%) developed new-onset diabetes mellitus. The odds of developing diabetes mellitus increased across increasing quartiles of copeptin, even after additional adjustment for baseline fasting glucose and insulin (adjusted odds ratios, 1.0, 1.37, 1.79, and 2.09; P for trend=0.004). The association with incident diabetes mellitus remained significant in analyses restricted to subjects with fasting whole blood glucose <5.4 mmol/L at baseline (adjusted odds ratios, 1.0, 1.80, 1.92, and 3.48; P=0.001). CONCLUSIONS: Elevated copeptin predicts increased risk for diabetes mellitus independently of established clinical risk factors, including fasting glucose and insulin. These findings could have implications for risk assessment, novel antidiabetic treatments, and metabolic side effects from arginine vasopressin system modulation.
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| 39. |
- Fawad, Ayesha, et al.
(författare)
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1C.07: PRONEUROTENSIN INDEPENDENTLY PREDICTS CARDIOVASCULAR DISEASE. THE MALMÖ PREVENTIVE PROJECT.
- 2015
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Ingår i: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 1473-5598 .- 0263-6352. ; 33 Suppl 1, s. 11-11
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Tidskriftsartikel (refereegranskat)abstract
- Neurotensin is released from the gut after fat intake and has a role in appetite regulations. Proneurotensin is a stable fragment of the neurotensin precursor hormone and fasting plasma proneurotensin levels have shown to be significantly associated with the development of cardiovascular disease in middle aged participants of the Malmö Diet and Cancer Study. Here, we aimed at replicating the initial findings in an independent second cohort and to extend its validity to an older population.
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| 40. |
- Fawad, Ayesha, et al.
(författare)
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Magnitude of rise in proneurotensin is related to amount of triglyceride appearance in blood after standardized oral intake of both saturated and unsaturated fat
- 2020
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Ingår i: Lipids in Health and Disease. - : Springer Science and Business Media LLC. - 1476-511X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown. AIM: To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals. SETTING/ METHODS: Twenty-two healthy subjects were given 150 mL of full milk cream (54 g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 h (h) and at 1 h, 2 h and 4 h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides. RESULTS: An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12-31) pmol/L (P < 0.001) and at 3 h for triglycerides of 0.60 (0.43-0.78) mmol/L (P < 0.001). Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46-78) pmol/L (P < 0.001) and plasma triglycerides at 3 h of 0.32 (0.18-0.45) mmol/L (P < 0.001). The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r = 0.49, P = 0.021) and olive oil (r = 0.55, P = 0.008), respectively. CONCLUSION: Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.
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