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Sökning: WFRF:(Ikram M Arfan)

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61.
  • Chauhan, Ganesh, et al. (författare)
  • Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies
  • 2016
  • Ingår i: The Lancet Neurology. - 1474-4465 .- 1474-4422. ; 15:7, s. 695-707
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq. © 2016 Elsevier Ltd
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62.
  • Climaco Pinto, Rui, et al. (författare)
  • Finding Correspondence between Metabolomic Features in Untargeted Liquid Chromatography-Mass Spectrometry Metabolomics Datasets.
  • 2022
  • Ingår i: Analytical chemistry. - : American Chemical Society (ACS). - 1520-6882 .- 0003-2700. ; 94:14, s. 5493-5503
  • Tidskriftsartikel (refereegranskat)abstract
    • Integration of multiple datasets can greatly enhance bioanalytical studies, for example, by increasing power to discover and validate biomarkers. In liquid chromatography-mass spectrometry (LC-MS) metabolomics, it is especially hard to combine untargeted datasets since the majority of metabolomic features are not annotated and thus cannot be matched by chemical identity. Typically, the information available for each feature is retention time (RT), mass-to-charge ratio (m/z), and feature intensity (FI). Pairs of features from the same metabolite in separate datasets can exhibit small but significant differences, making matching very challenging. Current methods to address this issue are too simple or rely on assumptions that cannot be met in all cases. We present a method to find feature correspondence between two similar LC-MS metabolomics experiments or batches using only the features' RT, m/z, and FI. We demonstrate the method on both real and synthetic datasets, using six orthogonal validation strategies to gauge the matching quality. In our main example, 4953 features were uniquely matched, of which 585 (96.8%) of 604 manually annotated features were correct. In a second example, 2324 features could be uniquely matched, with 79 (90.8%) out of 87 annotated features correctly matched. Most of the missed annotated matches are between features that behave very differently from modeled inter-dataset shifts of RT, MZ, and FI. In a third example with simulated data with 4755 features per dataset, 99.6% of the matches were correct. Finally, the results of matching three other dataset pairs using our method are compared with a published alternative method, metabCombiner, showing the advantages of our approach. The method can be applied using M2S (Match 2 Sets), a free, open-source MATLAB toolbox, available at https://github.com/rjdossan/M2S.
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63.
  • Freak-Poli, Rosanne, et al. (författare)
  • Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts
  • 2022
  • Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 85:1, s. 295-308
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health.Objective: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association.Methods: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71 +/- 7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72 +/- 10SD years) followed up to 10 years (mean 5.9 +/- 1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) >= 26 for RS and >= 25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor).Results: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95% CI 1.08-1.67; SNAC-K: HR 2.16, 95% CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk.Conclusion: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.
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64.
  • Khalili, Bita, et al. (författare)
  • Associations between common genetic variants and income provide insights about the socioeconomic health gradient
  • 2024
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient (N=668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic index captures 1 - 4% of income variance, with only one-fourth attributed to direct genetic effects. A phenome-wide association study using this polygenic index showed reduced risks for a broad spectrum of diseases, including hypertension, obesity, type 2 diabetes, coronary atherosclerosis, depression, asthma, and back pain. The income factor showed a substantial genetic correlation (0.92, s.e. = .006) with educational attainment (EA). Accounting for EA's genetic overlap with income revealed that the remaining genetic signal for higher income related to better mental health but reduced physical health benefits and increased participation in risky behaviours such as drinking and smoking.
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65.
  • Lenart-Bugla, Marta, et al. (författare)
  • What Do We Know about Social and Non-Social Factors Influencing the Pathway from Cognitive Health to Dementia? A Systematic Review of Reviews
  • 2022
  • Ingår i: Brain Sciences. - : MDPI AG. - 2076-3425 .- 2076-3425. ; 12:9
  • Forskningsöversikt (refereegranskat)abstract
    • The heterogeneous and multi-factorial nature of dementia requires the consideration of all health aspects when predicting the risk of its development and planning strategies for its prevention. This systematic review of reviews provides a comprehensive synthesis of those factors associated with cognition in the context of dementia, identifying the role of social aspects and evidencing knowledge gaps in this area of research. Systematic reviews and meta-analyses from 2009–2021 were searched for within Medline, PsycINFO, CINAHL Complete, Cochrane, and Epistemonikos. Reviewers independently screened, reviewed, and assessed the records, following the PRISMA-2020 guidelines. From 314 included studies, 624 cognitive-related factors were identified, most of them risk factors (61.2%), mainly belonging to the group of ‘somatic comorbidities’ (cardiovascular disease and diabetes) and ‘genetic predispositions’. The protective factors (20%) were mainly related to lifestyle, pointing to the Mediterranean diet, regular physical activity, and cognitively stimulating activities. Social factors constituted 9.6% of all identified factors. Research on biological and medical factors dominates the reviewed literature. Greater social support and frequent contact may confer some protection against cognitive decline and dementia by delaying its onset or reducing the overall risk; however, overall, our findings are inconsistent. Further research is needed in the fields of lifestyle, psychology, social health, and the protective factors against cognitive decline and dementia.
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66.
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67.
  • Repetto, Linda, et al. (författare)
  • Genetic mechanisms of 184 neuro-related proteins in human plasma.
  • 2023
  • Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.
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68.
  • Repetto, Linda, et al. (författare)
  • Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.
  • 2023
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
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69.
  • Tschiderer, Lena, et al. (författare)
  • Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque : Individual Participant Data Meta-Analysis of 20 Prospective Studies
  • 2023
  • Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980 .- 2047-9980. ; 12:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development.Methods and Results: We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I-2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I-2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I-2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques).Conclusions: Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.
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70.
  • van der Velpen, Isabelle F., et al. (författare)
  • Psychosocial health modifies associations between HPA-axis function and brain structure in older age
  • 2023
  • Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 153
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Dysregulation of the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis may have damaging effects on the brain, potentially under influence of psychosocial health factors. We studied associations between functioning of the negative feedback loop of HPA-axis, measured with a very low-dose dexamethasone suppression test (DST), and brain structure in middle-aged and older adults, and whether these associations were modified by psychosocial health.Methods: From 2006 to 2008, 1259 participants (mean age 57.6 +/- 6.4, 59.6 % female) of the population-based Rotterdam Study completed a very low-dose DST (0.25 mg) and underwent magnetic resonance imaging (MRI) of the brain. Self-reported psychosocial health (depressive symptoms, loneliness, marital status, perceived social support) were assessed in the same time period. Multivariable linear and logistic regression were used to study cross-sectional associations between cortisol response and brain volumetrics, cerebral small vessel disease markers and white matter structural integrity. To assess the effect of psychosocial health on these associations, analyses were further stratified for psychosocial health markers.Results: Cortisol response was not associated with markers of global brain structure in the overall study sample. However, in participants with clinically relevant depressive symptoms, a diminished cortisol response was associated with smaller white matter volume (mean difference: - 1.00 mL, 95 %CI = - 1.89;- 0.10) and smaller white matter hyperintensity volume (mean difference: - 0.03 mL (log), 95 %CI = - 0.05;0.00). In participants with low/moderate perceived social support compared to those with high social support, a diminished cortisol response was associated with larger gray matter volume (mean difference: 0.70 mL, 95 %CI = 0.01;1.39) and higher fractional anisotropy (standardized mean difference 0.03, 95 %CI = 0.00;0.06).Conclusion: Diminished function of the HPA-axis is differently associated with brain structure in communitydwelling middle-aged and older adults with clinically relevant depressive symptoms or suboptimal social support, but not in adults without depressive symptoms or with optimal social support.
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