| 51. |
- Natunen, Teemu, et al.
(författare)
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Elucidation of the BACE1 Regulating Factor GGA3 in Alzheimer's Disease
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 37:1, s. 217-232
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Tidskriftsartikel (refereegranskat)abstract
- Golgi-localized gamma-ear-containing ADP-ribosylation factor-binding protein (GGA3) is a central regulator of trafficking and degradation of BACE1 (beta-site A beta PP-cleaving enzyme), the rate-limiting enzyme in the production of amyloid-beta (A beta) in Alzheimer's disease (AD). Here, we assessed the potential role of GGA3 in AD pathogenesis using independent neuropathological, case-control, and family-based human sample cohorts. Increased BACE1 levels coincided with decreased GGA3 levels and with elevated phosphorylation status of eIF2 alpha-Ser51 in the temporal cortex of AD patients as compared to age-matched controls. Severity of the disease did not alter mRNA or protein levels of GGA3 in the inferior temporal cortex of AD patients, while a positive correlation between GGA3 and the levels of total, but not phosphorylated, tau was observed. Genetically, we did not observe consistent evidence for association between AD risk and common GGA3 polymorphisms across a number of independent sample cohorts. However, a nominally significant association was observed with rs2242230 (p < 0.05) among the Finnish case-control cohort. Accordingly, mRNA and protein levels of GGA3 in the inferior temporal cortex of AD patients did not significantly correlate with rs2242230 genotype status. While the present study indicates that GGA3 is involved in the cellular processes relevant for AD pathogenesis, the genetic data do not support the idea that common GGA3 polymorphisms would contribute to AD risk.
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| 52. |
- Neumann, Alexander, et al.
(författare)
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Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.
- 2023
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Ingår i: Genome medicine. - 1756-994X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n=205 controls, n=546 mild cognitive impairment, n=222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analysesof the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
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| 53. |
- Panyard, Daniel J., et al.
(författare)
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Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3
- 2024
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Ingår i: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 x 10(-5)) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 x 10(-7)). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 x 10(-6)) and CSF p-tau levels (P = 4.38 x 10(-9)). DISCUSSION These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels.
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| 54. |
- Savarese, Gianluigi, et al.
(författare)
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Association between renin-angiotensin system inhibitor use and mortality/morbidity in elderly patients with heart failure with reduced ejection fraction: a prospective propensity score matched cohort study
- 2018
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Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 39:48, s. 4257-4265
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Tidskriftsartikel (refereegranskat)abstract
- Aims In heart failure with reduced ejection fraction (HFrEF), renin angiotensin system inhibitors (RASi) improve morbidity and mortality. However, patients aged amp;gt;80 years constituted a small minority in trials. We assessed the association between RASi use and mortality/morbidity in HFrEF patients aged amp;gt;80 years. Methods and results We included patients with ejection fraction amp;lt;40% and age amp;gt;80 years from the Swedish Heart Failure Registry. Propensity scores for RASi use were calculated from 37 variables. Cox regression models for RASi vs. non-RASi with all-cause mortality and all-cause mortality/heart failure (HF) hospitalization as outcomes were fitted in a 1:1 propensity-score-matched cohort. To assess consistency, the same analyses were performed in a positive control cohort aged amp;lt;= 80 years. Of 6710 patients [median age (interquartile range) 85 (82-87) years; 38% women], 5384 (80%) received RASi. Propensity-score matching yielded 2416 patients, [age 86 (83-91) years]. RASi use was associated with hazard ratio (HR) (95% confidence interval) 0.78 (0.72-0.86) for all-cause mortality and 0.86 (0.79-0.94) for all-cause mortality/HF hospitalization. In positive control patients aged amp;lt;= 80 years (17 842 patients in the overall cohort, 2126 after matching), HR for all-cause mortality was 0.81 (0.71-0.91), whereas it was 0.85 (0.76-0.94) for all-cause mortality/HF hospitalization. Conclusion In HFrEF patients with age amp;gt;80years, RASi were relatively underused compared with in younger patients, despite similar association with reduced morbidity and mortality and no apparent association with risk of syncope-related hospitalization. These results may be interpreted as hypothesis generating for randomized clinical trials on RASi in this elderly HFrEF subpopulation.
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| 55. |
- Savarese, Gianluigi, et al.
(författare)
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Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction : an analysis of 11 215 patients from the Swedish Heart Failure Registry
- 2018
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Ingår i: European Journal of Heart Failure. - : John Wiley & Sons. - 1388-9842 .- 1879-0844. ; 20:9, s. 1326-1334
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF), but are underutilized. Hyperkalaemia may be one reason, but the underlying reasons for underuse are unknown. The aim of this study was to investigate the independent predictors of MRA underuse in a large and unselected HFrEF cohort.METHODS AND RESULTS: We included patients with HFrEF (ejection fraction <40%), New York Heart Association (NYHA) class II-IV and heart failure (HF) duration ≥6 months from the Swedish HF Registry. Logistic regression analysis identified independent associations between 39 demographic, clinical, co-treatment, and socioeconomic predictors and MRA non-use. Of 11 215 patients, 27% were women; mean age was 75 ± 11 years; only 4443 (40%) patients received MRA. Selected characteristics independently associated with MRA non-use were in descending order of magnitude: lower creatinine clearance (<60 mL/min), no need for diuretics, no cardiac resynchronization therapy/implantable cardioverter-defibrillator, higher blood pressure, no digoxin use, higher ejection fraction, outpatient setting, older age, lower income, ischaemic heart disease, male sex, follow-up in primary vs. specialty care, lower NYHA class, and absence of hypertension diagnosis. Plasma potassium and N-terminal pro B-type natriuretic peptide levels were not associated with MRA non-use.CONCLUSION: Mineralocorticoid receptor antagonists remain underused in HFrEF. Their use does not decrease with elevated potassium but does with impaired renal function, even in the creatinine clearance 30-59.9 mL/min range where MRAs are not contraindicated. MRA underuse may be further related to non-specialist care, milder HF and no use of other HF therapy.
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| 56. |
- Savarese, Gianluigi, et al.
(författare)
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Incidence, Predictors, and Outcome Associations of Dyskalemia in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction
- 2019
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Ingår i: JACC. Heart failure. - : ELSEVIER SCI LTD. - 2213-1779 .- 2213-1787. ; 7:1, s. 65-76
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES This study investigated 1-year incidence and predictors of dyskalemia (dysK) and its outcome associations in heart failure with preserved ejection fraction (HFpEF), HF with mid-range EF (HFmrEF), and HF with reduced EF (HFrEF). BACKGROUND DysK in real-world HF is insufficiently characterized. Fear of dyskalemia may lead to underuse or underdosing of renin-angiotensin-aldosterone system inhibitors. METHODS Patients enrolled in the SwedeHF (Swedish Heart Failure) Registry from 2006 to 2011 in Stockholm, Sweden were included in the analyses. Multivariate Cox regression analysis identified independent predictors of dysK within 1 year. Time-dependent Cox models assessed outcomes associated with incident dysK (all-cause death, HF, and other cardiovascular disease [CVD] hospitalizations) within 1 year from baseline. RESULTS Of 5,848 patients, 24.4% experienced hyperkalemia (hyperK [K amp;gt; 5.0 mmol/l]) at least once, and 10.2% had moderate or severe hyperK (K amp;gt; 5.5 mmol/l). Adjusted risk of moderate or severe hyperK was highest in HFpEF and HFmrEF. Similarly, 20.3% of patients had at least one episode of hypokalemia (hypoK [amp;lt;3.5 mmol/l]), and 3.7% had severe hypoK (amp;lt;3.0 mmol/l). Adjusted risk of any hypoK was highest in HFpEF. Independent predictors of both hyperK and hypoK were sex, baseline potassium and estimated glomerular filtration rate, low hemoglobin, chronic obstructive pulmonary disease (COPD), inpatient status, and higher New York Heart Association functional class. Incident dysK was associated with increased risk of mortality. Furthermore, hypoK was associated with increased CVD hospitalizations (HF-related excluded). There was no association between dysK and HF hospitalization risk, regardless of EF. CONCLUSIONS DysK is common in HF and is associated with increased mortality. Risk of moderate or severe hyperK was highest in HFpEF and HFmrEF, whereas risk of hypoK was highest in HFpEF. HF severity, low hemoglobin, COPD, baseline high and low potassium, and low eGFR were relevant predictors of dysK occurrence. (C) 2019 by the American College of Cardiology Foundation.
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| 57. |
- Schroeder, Julia, et al.
(författare)
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MicroRNA-138 is a potential regulator of memory performance in humans
- 2014
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Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media SA. - 1662-5161. ; 8, s. 501-
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors underlie a substantial proportion of individual differences in cognitive functions in humans, including processes related to episodic and working memory. While genetic association studies have proposed several candidate memory genes, these currently explain only a minor fraction of the phenotypic variance. Here, we performed genome-wide screening on 13 episodic and working memory phenotypes in 1318 participants of the Berlin Aging Study II aged 60 years or older. The analyses highlight a number of novel single nucleotide polymorphisms (SNPs) associated with memory performance, including one located in a putative regulatory region of microRNA (miRNA) hsa-mir-138-5p (rs9882688, P-value = 7.8 x 10(-9)). Expression quantitative trait locus analyses on next-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines (P-value = 5 x 10(-4)). In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3' untranslated region (3' UTR) of DCP1B, a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3' UTR reporter constructs in two human cell lines (HEK293: P-value = 0.0470; SH-SY5Y: P-value = 0.0866). Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo. In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory function.
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| 58. |
- Sharma, Manu, et al.
(författare)
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Large-scale replication and heterogeneity in Parkinson disease genetic loci
- 2012
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Ingår i: Neurology. - 1526-632X. ; 79:7, s. 67-659
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
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| 59. |
- Shi, Liu, et al.
(författare)
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Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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| 60. |
- Shi, Liu, et al.
(författare)
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Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.
- 2019
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 15:11, s. 1478-1488
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Tidskriftsartikel (refereegranskat)abstract
- Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.4001 plasma proteins were measured in two groups of participants (discovery group=516, replication group=365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.A panel of proteins (n=44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve=0.78) and the replication group (area under the curve=0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
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