| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
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| 3. |
- Nordentoft, Mads, et al.
(författare)
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Effort-reward imbalance at work and weight changes in a nationwide cohort of workers in Denmark
- 2020
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Ingår i: American Journal of Industrial Medicine. - : Wiley. - 0271-3586 .- 1097-0274. ; 63:7, s. 634-643
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the relation between effort-reward imbalance (ERI) at work and subsequent weight changes.Methods: We included participants from a population-based cohort of workers in Denmark (mean age = 47 years, 54% women) with two (n = 9005) or three repeated measurements (n = 5710). We investigated the association between (a) ERI (ie, the mismatch between high efforts spent and low rewards received at work) at baseline and weight changes after a 2-year follow-up (defined as >= 5% increase or decrease in body mass index (BMI) vs stable), and (b) onset and remission of ERI and subsequent changes in BMI. Using multinomial logistic regression we calculated risk ratios (RR) and 95% confidence intervals (CI), adjusted for sex, age, education, cohabitation, migration background, and follow-up time.Results: After 2 years, 15% had an increase and 13% a decrease in BMI. Exposure to ERI at baseline yielded RRs of 1.09 (95% CI: 0.95-1.25) and 1.04 (95% CI: 0.90-1.20) for the increase and decrease in BMI, respectively. There were no differences between sex and baseline BMI in stratified analyses. The onset of ERI yielded RRs of 1.04 (95% CI: 0.82-1.31) and 1.15 (95% CI: 0.84-1.57) for subsequent increase and decrease in BMI. The RRs for the remission of ERI and subsequent increase and decrease in BMI were 0.92 (95% CI: 0.71-1.20) and 0.78 (95% CI: 0.53-1.13), respectively. Of the ERI components, high rewards were associated with a lower risk of BMI increase.Conclusion: ERI was not a risk factor for weight changes. Future studies may investigate whether this result is generalizable to other occupational cohorts and settings.
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| 4. |
- Skovbakke, Sarah Line, et al.
(författare)
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The proteolytically stable peptidomimetic Pam-(Lys-βNSpe)6-NH2 selectively inhibits human neutrophil activation via formyl peptide receptor 2.
- 2015
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Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 93:2, s. 182-195
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Tidskriftsartikel (refereegranskat)abstract
- Immunomodulatory host defense peptides (HDPs) are considered to be lead compounds for novel anti-sepsis and anti-inflammatory agents. However, development of drugs based on HDPs has been hampered by problems with toxicity and low bioavailability due to in vivo proteolysis. Here, a subclass of proteolytically stable HDP mimics consisting of lipidated α-peptide/β-peptoid oligomers was investigated for their effect on neutrophil function. The most promising compound, Pam-(Lys-βNSpe)6-NH2, was shown to inhibit formyl peptide receptor 2 (FPR2) agonist-induced neutrophil granule mobilization and release of reactive oxygen species. The potency of Pam-(Lys-βNSpe)6-NH2 was comparable to that of PBP10, the most potent FPR2-selective inhibitor known. The immunomodulatory effects of structural analogs of Pam-(Lys-βNSpe)6-NH2 emphasized the importance of both the lipid and peptidomimetic parts. By using imaging flow cytometry in primary neutrophils and FPR-transfected cell lines, we found that a fluorescently labeled analog of Pam-(Lys-βNSpe)6-NH2 interacted selectively with FPR2. Furthermore, the interaction between Pam-(Lys-βNSpe)6-NH2 and FPR2 was found to prevent binding of the FPR2-specific activating peptide agonist Cy5-WKYMWM, while the binding of an FPR1-selective agonist was not inhibited. To our knowledge, Pam-(Lys-βNSpe)6-NH2 is the first HDP mimic found to inhibit activation of human neutrophils via direct interaction with FPR2. Hence, we consider Pam-(Lys-βNSpe)6-NH2 to be a convenient tool in the further dissection of the role of FPR2 in inflammation and homeostasis as well as for investigation of the importance of neutrophil stimulation in anti-infective therapy involving HDPs.
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