| 61. |
- Nowak, Christoph, et al.
(författare)
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Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.
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| 62. |
- Nowak, Christoph, et al.
(författare)
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Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes
- 2018
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Ingår i: Diabetologia. - : SPRINGER. - 0012-186X .- 1432-0428. ; 61:8, s. 1748-1757
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. Methods We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. Results Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (+/- SD) of 6.4 +/- 2.3 years. We replicated associations (< 5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit alpha (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. Conclusions/interpretation We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.
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| 63. |
- Nowak, Christoph, et al.
(författare)
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Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:1, s. 276-284
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.
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| 64. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 65. |
- Pagnon de la Vega, María, et al.
(författare)
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Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
- 2024
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Ingår i: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.
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| 66. |
- Pagnon de la Vega, María, 1994-
(författare)
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Characterization of the novel “Uppsala mutation” causing a familial form of early onset Alzheimer’s disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Alzheimer’s disease (AD) brain displays extracellular plaques of amyloid-β (Aβ), neurofibrillary tangles of tau and neuronal loss. The 40-42 amino acid Aβ peptide is formed from the amyloid precursor protein (APP) by β-secretase and γ-secretase, while α-secretase prevents Aβ generation. According to the amyloid cascade hypothesis, AD is initiated by increased brain levels of toxic Aβ species. Our laboratory has previously identified two APP mutations, causing early onset AD. Whereas the Swedish mutation results in increased β-secretase cleavage leading to higher Aβ levels, the Arctic mutation leads to a conformational Aβ change that promotes formation of toxic Aβ protofibrils.In this thesis, we have performed a screen for novel disease-causing mutations in 102 patients with early onset dementia disorders, who underwent investigation at the Memory clinic at Uppsala University Hospital. Mainly, we found a new APP mutation, which causes familial dominantly inherited AD with age at symptom onset in the early forties. This Uppsala APP mutation, consists of an intra-Aβ deletion of six consecutive amino acids, which results in Aβ with 34-36 amino acids (AβUppΔ19-24).Affected mutation-carriers develop symptoms typical of AD. As for biomarkers, the patients display expected changes although brain Aβ imaging by [11C]PIB-PET is only slightly pathological and Aβ42-analysis of cerebrospinal fluid yields normal results. By investigating neuropathological, biochemical and structural properties of AβUppΔ19-24 in patient samples, on synthetic peptides and in cell culture models we found evidence that Uppsala APP is pathogenic via three mechanisms: increased β-secretase cleavage, altered α-secretase cleavage and rapid formation of Aβ fibrils into unique polymorphs.To allow for in vivo studies of molecular mechanisms related to the Uppsala APP mutation we generated transgenic mice, expressing human APP with this mutation together with Swedish APP (to increase Aβ levels). In the brain of tg-UppSwe mice, we observed diffuse aggregates of mainly AβUpp42Δ19-24, which, given their normal γ-secretase activity, distinguishes these mice from most transgenic mouse models. In order to study if AβUppΔ19-24 co-aggregates with wild-type Aβ (Aβwt), we crossed tg-UppSwe with tg-Swe. Analyses of brains from such mice indicated that AβUppΔ19-24 may act as seeds for Aβwt by changing its aggregation behavior and thereby increasing its deposition in brain.Taken together, our studies of the Uppsala APP mutation have provided new knowledge of pathogenic molecular mechanisms in AD and of basic Aβ biology. Such insights may in a longer perspective help us to develop new diagnostics and therapeutics for this disorder.
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| 67. |
- Pagnon de la Vega, María, 1994-, et al.
(författare)
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Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer’s disease and frontotemporal dementia
- 2022
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Ingår i: BMC Genomics. - : Springer Nature. - 1471-2164. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most dementia disorders have a clear genetic background and a number of disease genes have beenidentified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genesfor the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inheritedforms of Alzheimer’s disease (AD).Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects ofsuch mutations have proven important for understanding the pathogenic processes. Here, we performed a screen toidentify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation.Results: Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes(PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, otherdementia diagnoses or mild cognitive impairment.We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met-146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation,named the Uppsala mutation, consists of a six amino acid intra-amyloid β deletion.In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4was prevalent in this patient group with an allele frequency of 54%Conclusions: Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP,as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart fromgiving important information to the clinical investigation, the identification of disease mutations can contribute to anincreased understanding of disease mechanisms.
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