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Sökning: WFRF:(Donnelly Peter)

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11.
  • Manning, Alisa, et al. (författare)
  • A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
  • 2017
  • Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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13.
  • Bellenguez, Celine, et al. (författare)
  • Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
  • 2012
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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14.
  • Ederth, Thomas, et al. (författare)
  • Resistance of Galactoside-Terminated Alkanethiol Self-Assembled Monolayers to Marine Fouling Organisms
  • 2011
  • Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society. - 1944-8244 .- 1944-8252. ; 3:10, s. 3890-3901
  • Tidskriftsartikel (refereegranskat)abstract
    • Self-assembled monolayers (SAMs) of galactoside-terminated alkanethiols have protein-resistance properties which can be tuned via the degree of methylation [Langmuir 2005, 21, 2971-2980]. Specifically, a partially methylated compound was more resistant to nonspecific protein adsorption than the hydroxylated or fully methylated counterparts. We investigate whether this also holds true for resistance to the attachment and adhesion of a range of marine species, in order to clarify to what extent resistance to protein adsorption correlates with the more complex adhesion of fouling organisms. The partially methylated galactoside-terminated SAM was further compared to a mixed monolayer of omega-substituted methyl- and hydroxyl-terminated alkanethiols with wetting properties and surface ratio of hydroxyl to methyl groups matching that of the galactoside. The settlement (initial attachment) and adhesion strength of four model marine fouling organisms were investigated, representing both micro- and macrofoulers; two bacteria (Cobetia marina and Marinobacter hydrocarbonoclasticus), barnacle cypris larvae (Balanus amphitrite), and algal zoospores (Ulva linza). The minimum in protein adsorption onto the partially methylated galactoside surface was partly reproduced in the marine fouling assays, providing some support for a relationship between protein resistance and adhesion of marine fouling organisms. The mixed alkanethiol SAM, which was matched in wettability to the partially methylated galactoside SAM, consistently showed higher settlement (initial attachment) of test organisms than the galactoside, implying that both wettability and surface chemistry are insufficient to explain differences in fouling resistance. We suggest that differences in the structure of interfacial water may explain the variation in adhesion to these SAMs.
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15.
  • Howells, Tim, et al. (författare)
  • Optimal Cerebral Perfusion Pressure in Centers With Different Treatment Protocols
  • 2018
  • Ingår i: Critical Care Medicine. - : LIPPINCOTT WILLIAMS & WILKINS. - 0090-3493 .- 1530-0293. ; 46:3, s. e235-e241
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: The three centers in this study have different policies regarding cerebral perfusion pressure targets and use of vasopressors in traumatic brain injury patients. The aim was to determine if the different policies affected the estimation of cerebral perfusion pressure which optimizes the strength of cerebral autoregulation, termed "optimal cerebral perfusion pressure." Design: Retrospective analysis of prospectively collected data. Setting: Three neurocritical care units at university hospitals in Cambridge, United Kingdom, Groningen, the Netherlands, and Uppsala, Sweden. Patients: A total of 104 traumatic brain injury patients were included: 35 each from Cambridge and Groningen, and 34 from Uppsala. Interventions: None. Measurements and Main Results: In Groningen, the cerebral perfusion pressure target was greater than or equal to 50 and less than 70mm Hg, in Uppsala greater than or equal to 60, and in Cambridge greater than or equal to 60 or preferably greater than or equal to 70. Despite protocol differences, median cerebral perfusion pressure for each center was above 70mm Hg. Optimal cerebral perfusion pressure was calculated as previously published and implemented in the Intensive Care Monitoring+ software by the Cambridge group, now replicated in the Odin software in Uppsala. Periods with cerebral perfusion pressure above and below optimal cerebral perfusion pressure were analyzed, as were absolute difference between cerebral perfusion pressure and optimal cerebral perfusion pressure and percentage of monitoring time with a valid optimal cerebral perfusion pressure. Uppsala had the highest cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Uppsala patients were older than the other centers, and age is positively correlated with cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Optimal cerebral perfusion pressure was significantly lower in Groningen than in Cambridge. There were no significant differences in percentage of monitoring time with valid optimal cerebral perfusion pressure. Summary optimal cerebral perfusion pressure curves were generated for the combined patient data for each center. These summary curves could be generated for Groningen and Cambridge, but not Uppsala. The older age of the Uppsala patient cohort may explain the absence of a summary curve. Conclusions: Differences in optimal cerebral perfusion pressure calculation were found between centers due to demographics (age) and treatment (cerebral perfusion pressure targets). These factors should be considered in the design of trials to determine the efficacy of autoregulation-guided treatment.
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16.
  • Lappalainen, Tuuli, et al. (författare)
  • Transcriptome and genome sequencing uncovers functional variation in humans
  • 2013
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 501:7468, s. 506-511
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project-the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.
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18.
  • Peden, John F., et al. (författare)
  • A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
  • 2011
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
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19.
  • Sawcer, Stephen, et al. (författare)
  • Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
  • 2011
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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20.
  • Stitziel, Nathan O., et al. (författare)
  • Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
  • 2016
  • Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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