| 211. |
- Wu, Ping-Hsun, 1982-
(författare)
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Influence of bone-associated and cardiovascular biomarkers on vascular events and mortality in relation to renal dysfunction
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Biomarkers can help physicians identify subjects with an increased cardiovascular risk. Apart from the clinical factors, some biomarkers have been recognized as important predictors and risk factors for cardiovascular disease in renal disease. The applicability of biomarkers may be limited in patients with kidney disease due to the complex etiology of cardiovascular disease, which warrants separate evaluations, including established and novel biomarkers. The overall aim of the thesis was to investigate the association between bone-associated markers and cardiovascular proteins on death and vascular events in the elderly male population and patients with kidney disease.Study I included 3,014 participants in Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort and investigated the associations between Klotho single-nucleotide polymorphism and mortality. Two potentially damaging single-nucleotide polymorphisms (rs9536314 and rs9527025) in the Klotho gene were not associated with mortality.Study II investigated the association between mineral bone markers and all-cause mortality / cardiovascular mortality. The composite evaluation of elevated fibroblast growth factor-23 levels, vitamin D deficiency, and renal impairment was associated with mortality.Study III evaluated the bone-associated proteins and mortality/composite vascular events in the 331 Demark hemodialysis patients. Osteoprotegerin, as one of the most promising bone-related proteins, was associated with composite vascular events independent of cytokine.Study IV investigated the association between 92 proteins measured by proximity extension assay and mortality/composite vascular events in hemodialysis patients. A higher level of Interleukin-8, T-cell immunoglobulin and mucin domain 1, C-C motif chemokine 20, and lower level of stem cell factor and galanin peptides were associated with poor outcomes.This thesis addressed the issue of bone-vascular axis and cardiovascular disease. We evaluated from gene levels to circulating protein levels and from the general population to patients with kidney disease. Based on our research findings, more evidence was linked between bone and vascular complications. We also identified several cardiovascular proteins considered potentially important predictors for cardiovascular disease in patients with renal failure, especially hemodialysis patients.
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| 212. |
- Wu, Ping-Hsun, 1982-, et al.
(författare)
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Novel biomarkers detected by proteomics predict death and cardiovascular events in hemodialysis patients
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background. End-stage kidney disease increases mortality and the risk of cardiovascular (CV) disease. It is crucial to explore novel biomarkers to predict CV disease in the complex setting of patients receiving hemodialysis (HD). This study investigated the association between 92 targeted proteins with all-cause death, CV death, and composite vascular events (CVEs) in HD patients.Methods. From December 2010 to March 2011, 331 HD patients were included and followed prospectively for 5 years. Serum was analyzed for 92 CV-related proteins using Proseek Multiplex Cardiovascular I panel, a high-sensitivity assay based on proximity extension assay (PEA) technology. The association between biomarkers and all-cause death, CV death, and CVEs was evaluated by Cox-regression analyses.Results. Of the PEA-based proteins, we identified 20 proteins associated with risk of all-cause death, 7 proteins associated with risk of CV death, and 17 proteins associated with risk of CVEs, independent of established risk factors. Interleukin-8 (IL-8), T-cell immunoglobulin and mucin domain 1 (TIM-1), and C-C motif chemokine 20 (CCL20) were associated with increased risk of all-cause death, CV death, and CVE in multivariable-adjusted models. Stem cell factor (SCF) and Galanin peptides (GAL) were associated with both decreased risk of all-cause death and CV death.Conclusions. IL-8, TIM-1, and CCL20 predicted death and CV outcomes in HD patients. Novel findings were that SCF and GAL were associated with a lower risk of all death and CV death. The SCF warrants further study with regards to its possible biological effect in HD patients.
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| 213. |
- Wu, Ping-Hsun, 1982-, et al.
(författare)
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Novel Biomarkers Detected by Proteomics Predict Death and Cardiovascular Events in Hemodialysis Patients
- 2022
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- End-stage kidney disease increases mortality and the risk of cardiovascular (CV) disease. It is crucial to explore novel biomarkers to predict CV disease in the complex setting of patients receiving hemodialysis (HD). This study investigated the association between 92 targeted proteins with all-cause death, CV death, and composite vascular events (CVEs) in HD patients. From December 2010 to March 2011, 331 HD patients were included and followed prospectively for 5 years. Serum was analyzed for 92 CV-related proteins using Proseek Multiplex Cardiovascular I panel, a high-sensitivity assay based on proximity extension assay (PEA) technology. The association between biomarkers and all-cause death, CV death, and CVEs was evaluated using Cox-regression analyses. Of the PEA-based proteins, we identified 20 proteins associated with risk of all-cause death, 7 proteins associated with risk of CV death, and 17 proteins associated with risk of CVEs, independent of established risk factors. Interleukin-8 (IL-8), T-cell immunoglobulin and mucin domain 1 (TIM-1), and C-C motif chemokine 20 (CCL20) were associated with increased risk of all-cause death, CV death, and CVE in multivariable-adjusted models. Stem cell factor (SCF) and Galanin peptides (GAL) were associated with both decreased risk of all-cause death and CV death. In conclusion, IL-8, TIM-1, and CCL20 predicted death and CV outcomes in HD patients. Novel findings were that SCF and GAL were associated with a lower risk of all-cause death and CV death. The SCF warrants further study with regard to its possible biological effect in HD patients.
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| 214. |
- Wu, Ping-Hsun, 1982-, et al.
(författare)
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Osteoprotegerin predicts cardiovascular events in patients treated with haemodialysis
- 2021
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 37:6, s. 1162-1170
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Tidskriftsartikel (refereegranskat)abstract
- Background: Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality, and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers, and the association with inflammatory cytokines, and cardiovascular outcomes.Methods: This prospective study enrolled hemodialysis (HD) patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1 (Dkk-1), fibroblast growth factor 23 (FGF-23), leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest algorithm (RF). The association between bone-associated proteins with all-cause death, cardiovascular death, and CVEs was analyzed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data, and dialysis duration.Results: We enrolled 331 patients (63.7% men; mean [SD] age, 65 [14.6] years) in a prospective cohort study with five years follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death, and four biomarkers were associated with CVE. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins, and just OPG remained associated with CVE in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVE when added clinical information alone in integrated discrimination improvement and net reclassification improvement analyses.Discussion: OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD, and CTSL1) was affected by cytokine inflammation activity.
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| 215. |
- Wu, Ping-Hsun, et al.
(författare)
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The association between Single Nucleotide Polymorphisms of Klotho Gene and Mortality in Elderly Men: The MrOS Sweden Study
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The Klotho (KL) gene is involved in phosphate homeostasis. Polymorphisms in this gene have been reported to be associated with the risk of cardiovascular disease. Here we used computational tools to predict the damage-associated single nucleotide polymorphisms (SNPs) in the human KL gene. We further investigated the association of SNPs in the KL gene and mortality in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort. This study included 2921 men (aged 69-81 years) with mean 4.49 +/- 1.03 years follow-up. 18 SNPs in the KL gene were genotyped using Sequenom. These SNPs were identified by in silico tools for the coding and noncoding genome to predict the damaging SNPs. After quality analyses, SNPs were analyzed for mortality risk using two steps approach on logistic regression model screening and then Cox regression model confirmation. Two non-synonymous SNPs rs9536314 and rs9527025 were found to be potentially damaging SNPs that affect KL protein stability and expression. However, these two SNPs were not statistically significantly associated with all-cause mortality (crude Hazard ratio [HR] 1.72, 95% confidence interval [CI] 0.96-3.07 in rs9536314; crude HR 1.82, 95% CI 0.998-3.33 in rs9527025) or cardiovascular mortality (crude HR 1.52, 95% CI 0.56-4.14 in rs9536314; crude HR 1.54, 95% CI 0.55-4.33 in rs9527025) in additive model using Cox regression analysis. In conclusion, these two potentially damaging SNPs (rs9536314 and rs9527025) in the KL gene were not associated with all-cause mortality or cardiovascular mortality in MrOs cohort. Larger scales studies and meta-analysis are needed to confirm the correlation between polymorphisms of the KL gene and mortality.
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| 216. |
- Wu, Ping-Hsun, 1982-, et al.
(författare)
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The effect of fibroblast growth factor 23, vitamin D, and renal function on all-cause and cardiovascular mortality : The MrOS Sweden Study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), estimated glomerular filtration rate (eGFR), and vitamin D have been linked to mortality and cardiovascular disease, but the limited data addressed the combined effect of these factors on mortality. We investigated these different aspects of mineral bone disease biomarkers that portray independent and prognostic information in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort.Methods: The baseline level of FGF23, PTH, vitamin D, and eGFR was categorized as a normal and abnormal group. The mortality risk of mineral bone markers was analyzed by Kaplan-Meier curve for group difference evaluation and restricted cubic regression spline curve for continuous values of markers. We compare the importance of markers by random forest. Cox proportional regression models were used to evaluate the mortality risk of abnormal mineral bone markers components and their independent effect.Results: The MrOS cohort included 2706 men whose mean aged 75.4±3.18 years, 9.4% had diabetes, and 36.3% had hypertension. During a mean follow-up of 4.48 years, 383 all-cause deaths and 144 cardiovascular deaths were recorded. A high intact FGF23 level, low eGFR, and vitamin D deficiency were associated with increased all-cause mortality. Participants with a combination of high FGF23 level, low eGFR, and vitamin D deficiency had a twofold increased all-cause and cardiovascular mortality risk compared to those without abnormalities after adjusting for confounders. FGF23 was the most important factor related to all-cause mortality in random forest analysis, but the association was attenuated after controlling eGFR in the Cox model. In contrast, a low vitamin D remained to predict all-cause mortality independently.Conclusions: A higher FGF23, lower renal function, and lower vitamin D level are associated with increased all-cause and cardiovascular mortality in elderly men. Renal dysfunction influenced the mortality prediction of FGF23 but not vitamin D.
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| 217. |
- Zayny, Ahmad, et al.
(författare)
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Effects of glucocorticoids on vitamin D3 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblasts
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to rickets, osteomalacia or osteoporosis. Long-term treatment with glucocorticoids is known to result in osteoporosis and a substantially increased risk of fractures. Although the actions of vitamin D and glucocorticoids play important roles for bone function and in the development of osteoporosis, much remains unclear regarding the effects of these compounds in cells of the bone. In the current study, the human osteosarcoma Saos-2 cell line and primary human osteoblast-like cells were found to express mRNA for the vitamin D receptor as well as both activating and deactivating enzymes in vitamin D3 metabolism. These bone cells exhibited the CYP24A1-mediated 24-hydroxylation, involved in deactivation of the active vitamin D3 form. However, bioactivating vitamin D3 hydroxylase activities could not be detected in either of these cells. Several commonly used therapeutic glucocorticoids, including prednisolone, down regulated mRNA expression for the CYP24A1 gene as well as the CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblast-like cells. Prednisolone had the strongest suppressive effect on CYP24A1 expression. Results from experiments with a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells, co-transfected with the glucocorticoid receptor, showed that treatment with prednisolone significantly suppresses the CYP24A1 promoter activity. Thus, the results of the present study showed suppression by glucocorticoids on expression of CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. As part of the present investigation we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid that has glucocorticoid activity and is able to bind to the glucocorticoid receptor.Our data showing suppression by glucocorticoids on CYP24A1 expression in human osteoblast-like cells suggest a previously unknown mechanism for effects of glucocorticoids in human bone, where these compounds may act by increasing the normal levels of active vitamin D.
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| 218. |
- Zayny, Ahmad, et al.
(författare)
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Effects of glucocorticoids on vitamin D3-metabolizing 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblasts
- 2019
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207 .- 1872-8057. ; 496
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D-3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation which is essential for deactivation of the active vitamin form. However, bioactivating vitamin D-3 hydroxylase activities could not be detected in either of these cells. Several glucocorticoids, including prednisolone, down regulated CYP24A1 mRNA and CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts. Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. As part of this study we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our data showing suppression by glucocorticoids on CYP24A1 expression in human osteoblasts suggest a previously unknown mechanism for effects of glucocorticoids in human bone, where these compounds may interfere with regulation of active vitamin D levels.
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| 219. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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