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Sökning: WFRF:(Strawbridge Rona J.)

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  • Föregående 1234[5]
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41.
  • Chernogubova, Ekaterina, et al. (författare)
  • Common and Low-Frequency Genetic Variants in the PCSK9 Locus Influence Circulating PCSK9 Levels
  • 2012
  • Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 32:6, s. 1526-1534
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that influences plasma low-density lipoprotein concentration and susceptibility to coronary heart disease. Circulating PCSK9 levels show considerable interindividual differences, but the factors responsible for this variation are largely unknown.Methods and Results- We analyzed circulating PCSK9 levels in 4 cohorts of healthy, middle-aged Swedes (n=5722) and found that PCSK9 levels varied over approximate to 50-fold range, showed a positive relationship with plasma low-density lipoprotein-cholesterol concentration, and were associated with plasma triglyceride, fibrinogen, insulin, and glucose concentrations. A genome-wide association study conducted in 2 cohorts (n=1215) failed to uncover common genetic variants robustly associated with variation in circulating PCSK9 level. As expected, the minor allele of the PCSK9 R46L variant was in all cohorts associated with reduced PCSK9 levels and decreased plasma low-density lipoprotein-cholesterol concentrations, but no relationship was observed with the plasma triglyceride concentration. Further mapping of the PCSK9 locus revealed a common polymorphism (rs2479415, minor allele frequency 43.9%), located approximate to 6 kb upstream from PCSK9, which is independently associated with increased circulating PCSK9 levels.Conclusion- Common and low-frequency genetic variants in the PCSK9 locus influence the pronounced interindividual variation in circulating PCSK9 levels in healthy, middle-aged white (predominantly Swedish) subjects.
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42.
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43.
  • Frånberg, Mattias, et al. (författare)
  • Fast and general tests of genetic interaction for genome-wide association studies
  • 2017
  • Ingår i: PloS Computational Biology. - 1553-734X. ; 13:6
  • Tidskriftsartikel (refereegranskat)abstract
    • A complex disease has, by definition, multiple genetic causes. In theory, these causes could be identified individually, but their identification will likely benefit from informed use of anticipated interactions between causes. In addition, characterizing and understanding interactions must be considered key to revealing the etiology of any complex disease. Large-scale collaborative efforts are now paving the way for comprehensive studies of interaction. As a consequence, there is a need for methods with a computational efficiency sufficient for modern data sets as well as for improvements of statistical accuracy and power. Another issue is that, currently, the relation between different methods for interaction inference is in many cases not transparent, complicating the comparison and interpretation of results between different interaction studies. In this paper we present computationally efficient tests of interaction for the complete family of generalized linear models (GLMs). The tests can be applied for inference of single or multiple interaction parameters, but we show, by simulation, that jointly testing the full set of interaction parameters yields superior power and control of false positive rate. Based on these tests we also describe how to combine results from multiple independent studies of interaction in a meta-analysis. We investigate the impact of several assumptions commonly made when modeling interactions. We also show that, across the important class of models with a full set of interaction parameters, jointly testing the interaction parameters yields identical results. Further, we apply our method to genetic data for cardiovascular disease. This allowed us to identify a putative interaction involved in Lp(a) plasma levels between two 'tag' variants in the LPA locus (p = 2.42 . 10(-09)) as well as replicate the interaction (p = 6.97 . 10(-07)). Finally, our meta-analysis method is used in a small (N = 16,181) study of interactions in myocardial infarction.
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44.
  • Paramel, Geena, 1985-, et al. (författare)
  • CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
  • 2013
  • Ingår i: Clinical Science. - London, United Kingdom : Portland Press. - 0143-5221. ; 125:8, s. 401-407
  • Tidskriftsartikel (refereegranskat)abstract
    • Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1 beta in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-kappa B (nuclear factor kappa B). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1 beta, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P < 0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.
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45.
  • Paramel Varghese, Geena, 1985-, et al. (författare)
  • NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
  • 2016
  • Ingår i: Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease. - Hoboken, USA : Wiley-Blackwell Publishing Inc.. - 2047-9980. ; 5:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.
46.
  • Sandling, Johanna K., et al. (författare)
  • A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE
  • 2011
  • Ingår i: European Journal of Human Genetics. - Nature Publishing Group. - 1476-5438. ; 19:4, s. 479-484
  • Tidskriftsartikel (refereegranskat)abstract
    • Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P < 0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P-meta=0.00010 and P-meta=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P-meta=3.3 x 10(-5)), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis. European Journal of Human Genetics (2011) 19, 479-484; doi:10.1038/ejhg.2010.197; published online 22 December 2010
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47.
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48.
  • Strawbridge, Rona J (författare)
  • Analysis of functional genetic polymorphisms in prostate cancer and type 2 diabetes : Mucin 1 and growth hormone receptor
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Prostate cancer and type 2 diabetes are complex diseases, the genetic and environmental basis of which are not well established. Epidimiology suggests a link between the two diseases, with type 2 diabetes redusing the risk of prostate cancer, and faily history of prostate cancer reducing the risk of type 2 diabetes. Common genetic variations are believed to influence risk of both diseases, with very little overlap between the genes implicated. Metabolism may be a link between the two diseases: diabetes is characterised by abberant utilization and storage of dietary energy, where as prostate cancer has a high demand for energy input. It is plausible that genes and thier variants which alter metabolic homeostasis influence risk of both diseases in the opposite directions. In order to investigate whether this hypothesis is correct, we investigated common genetic variation of two genes, GHR and MUC1, in prostate cancer and type 2 diabetes. Bothe genes have previously been implicated in prostate cancer, with some evidence suggesting a role for MUC1 as a biomarker for prostate cancer. The GH-IGF-I-Insulin axis is key to metabolism, thus is likely ot be important in diabetes. The suggestion of a role for MUC1 in type 2 diabetes is a novel. A number of MUC1 isoforms, some of which have been implicated in various cancers, are determined by a SNP in exon 2. Functional differences between the variants are as yet unknown. A polymorphism in the GHR where by exon 3 is excluded is believed to have increased bioactivity compared to the full length form, although this is much debated. In this thesis we demonstrated that the GHR exon 3 polyorphism reduces risk of type 2 diabetes, and is associated with increased BMI, CRP and IGF-I levels in diabetic subjects. The variant allele of MUC1 was associated with an increased risk of type 2 diabetes and lower IGF-I levels. Subjects homozygous for the variant allele had increased LDL and CRP levels In conclusion, these genetic variations of GHR and MUC1 have potential as biomarkers for type 2 diabetes, and its complications. Genetic variation of MUC1 in blood DNA samples does not influence prostate cancer risk or survival, however tumour-specific genetic alterations may be important. Sequence analysis indicates that MUC1 isoforms may have distinct differences.
49.
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