SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "WFRF:(Crawford E David) srt2:(2015-2019)"

Sökning: WFRF:(Crawford E David) > (2015-2019)

  • Resultat 1-10 av 12
  • [1]2Nästa
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  • de Jong, Simone, et al. (författare)
  • Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
  • 2018
  • Ingår i: Communications Biology. - Nature Publishing Group. - 2399-3642. ; 1
  • Tidskriftsartikel (refereegranskat)abstract
    • Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
2.
  • Jones, Gregory T., et al. (författare)
  • Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
  • 2017
  • Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 120:2, s. 341-
  • Tidskriftsartikel (refereegranskat)abstract
    • Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
3.
  • Gusev, Alexander, et al. (författare)
  • Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
  • 2016
  • Ingår i: Nature communications. - 2041-1723. ; 7, s. 10979
  • Tidskriftsartikel (refereegranskat)abstract
    • Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
4.
  • Block, Keith I., et al. (författare)
  • Designing a broad-spectrum integrative approach for cancer prevention and treatment
  • 2015
  • Ingår i: Seminars in Cancer Biology. - Academic Press. - 1044-579X. ; 35, s. S276-S304
  • Forskningsöversikt (övrigt vetenskapligt)abstract
    • Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
5.
  • Raghavan, Maanasa, et al. (författare)
  • Genomic evidence for the Pleistocene and recent population history of Native Americans
  • 2015
  • Ingår i: Science. - 0036-8075 .- 1095-9203. ; 349:6250
  • Tidskriftsartikel (refereegranskat)abstract
    • Howand when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericues and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
  •  
6.
  • Bernal, Ximena E., et al. (författare)
  • Empowering Latina scientists
  • 2019
  • Ingår i: Science. - 0036-8075. ; 363:6429, s. 825-826
  • Tidskriftsartikel (övrigt vetenskapligt)
  •  
7.
  • Freitag, Daniel F., et al. (författare)
  • Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
  • 2015
  • Ingår i: The Lancet Diabetes & Endocrinology. - Elsevier. - 2213-8595. ; 3:4, s. 243-253
  • Tidskriftsartikel (refereegranskat)abstract
    • Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
8.
  • van Setten, Jessica, et al. (författare)
  • PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
  • 2018
  • Ingår i: Nature Communications. - NATURE PUBLISHING GROUP. - 2041-1723 .- 2041-1723. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
9.
  • Chio, Iok In Christine, et al. (författare)
  • NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer
  • 2016
  • Ingår i: Cell. - 0092-8674. ; 166:4, s. 936-976
  • Tidskriftsartikel (refereegranskat)abstract
    • Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.
  •  
10.
  • Kim, Eric H., et al. (författare)
  • Detection of High Grade Prostate Cancer among PLCO Participants Using a Prespecified 4-Kallikrein Marker Panel
  • 2016
  • Ingår i: Journal of Urology. - Lippincott Williams & Wilkins. - 0022-5347.
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: We assessed the performance of a 4-kallikrein panel with and without microseminoprotein-β to predict high grade (Gleason 7+/Gleason Grade Group 2+) prostate cancer on biopsy in a multiethnic cohort from PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial). Materials and Methods: Levels of free, intact, total prostate specific antigen, human kallikrein-2 and microseminoprotein-β were measured while blinded to outcomes in cryopreserved serum from men in the intervention arm of PLCO. Marker levels of 946 men, of whom 100 were African American, were incorporated into a prespecified statistical model to predict high grade prostate cancer on biopsy. Results: The detection of high grade prostate cancer in 94 men (10%) was enhanced by the 4-kallikrein panel with an AUC of 0.79 compared to 0.73 for PCPTRC (Prostate Cancer Prevention Trial Risk Calculator), representing a 0.060 increase (95% CI 0.032-0.088, p <0.01). Additionally, the AUC increased from 0.79 to 0.81 when microseminoprotein-β was added to the 4-kallikrein panel. In African American men, the 4-kallikrein panel model also enhanced high grade prostate cancer detection over that of prostate specific antigen (AUC 0.80 vs 0.67). As an illustration of clinical implications, using 1 cutoff point for biopsy (6% risk of high grade prostate cancer) with the 4-kallikrein panel model would have eliminated unnecessary biopsies in 420 per 1,000 men (42%) while detecting high grade prostate cancer in 83 of 93 (88%). Conclusions: In a multiethnic United States population, the 4-kallikrein panel demonstrated improved risk discrimination for high grade prostate cancer over conventional clinical variables (age, prostate specific antigen and digital rectal examination) as well as PCPTRC.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-10 av 12
  • [1]2Nästa
Åtkomst
fritt online (6)
Typ av publikation
tidskriftsartikel (11)
forskningsöversikt (1)
Typ av innehåll
refereegranskat (9)
övrigt vetenskapligt (3)
Författare/redaktör
Landén, Mikael, 1966 ... (2)
Lilja, Hans, (1)
Haley, J. (1)
Kerr, K. (1)
Eriksson, Anders (1)
Betsholtz, Christer (1)
visa fler...
Auvinen, A (1)
Overvad, Kim (1)
Khaw, Kay-Tee (1)
Riboli, Elio (1)
Santos, J. (1)
Landen, M, (1)
Bergen, Sarah E (1)
Norman, Paul J. (1)
Parham, Peter (1)
Wang, L. (1)
Wilson, John, (1)
Murtola, T. (1)
Dabrosin, Charlotta, (1)
Malmberg, Anders, (1)
Neijber, Anders, (1)
Matthews, Keith, (1)
Raitakari, Olli T (1)
Johansson, JE (1)
Donovan, Jenny L (1)
Hamdy, Freddie C (1)
Neal, David E (1)
Eeles, Rosalind A (1)
Henderson, Brian E (1)
Haiman, Christopher ... (1)
Kote-Jarai, Zsofia (1)
Benlloch, Sara (1)
Muir, Kenneth (1)
Berndt, Sonja I (1)
Conti, David V (1)
Wiklund, Fredrik (1)
Gapstur, Susan M (1)
Stevens, Victoria L (1)
Batra, Jyotsna (1)
Clements, Judith A (1)
Pashayan, Nora (1)
Schleutker, Johanna (1)
Albanes, Demetrius (1)
Travis, Ruth C (1)
Giles, Graham G (1)
Kibel, Adam S (1)
Kogevinas, Manolis (1)
Park, Jong Y (1)
Stanford, Janet L (1)
Cybulski, Cezary (1)
visa färre...
Lärosäte
Uppsala universitet (4)
Karolinska Institutet (4)
Umeå universitet (3)
Göteborgs universitet (2)
Lunds universitet (2)
Linköpings universitet (1)
visa fler...
Chalmers tekniska högskola (1)
visa färre...
Språk
Engelska (12)
Forskningsämne (UKÄ/SCB)
Medicin och hälsovetenskap (11)
Naturvetenskap (2)

År

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy