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Sökning: WFRF:(Szulkin R)

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  • Dadaev, Tokhir, et al. (författare)
  • Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.
  • 2018
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
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  • Szulkin, Robert, et al. (författare)
  • Prediction of individual genetic risk to prostate cancer using a polygenic score.
  • 2015
  • Ingår i: The Prostate. - 0270-4137 .- 1097-0045. ; 75:13, s. 1467-74
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
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  • Borgstrom, E. W., et al. (författare)
  • CD4(+) T cell proliferative responses to PPD and CFP-10 associate with recent M. tuberculosis infection
  • 2020
  • Ingår i: Tuberculosis. - 1472-9792. ; 123, s. 101959-
  • Tidskriftsartikel (refereegranskat)abstract
    • Interferon-gamma release assays cannot differentiate latent from active tuberculosis (TB), nor identify the recently infected with increased risk of active disease. The objective of this study was to identify biomarkers of recent infection following exposure to tuberculosis, to increase the positive predictive value for incipient TB. Contacts to patients with pulmonary TB were tested repeatedly with interferon-gamma release assays and flow-cytometry. Proliferative CD4(+) T cell responses to purified protein derivative (PPD) and 11 M. tuberculosis antigens were analysed. The individual probability of recent and remote infection was estimated using clinical data in a novel mathematical model and compared with CD4(+) responses in a prediction model. The most specific prediction of recent infection was high CD4(+) proliferative responses to CFP-10 and PPD and a low CD4(+) response to ESAT-6. CD4(+) proliferative responses to Rec85a, Rec85b and Rv1284 were also observed in recent infection, but did not reach significance in the prediction model. Conclusions: High CD4(+) proliferative responses to CFP-10 and PPD and a low response to ESAT-6 may be used as biomarkers to improve positive predictive values for recent LTBI and thus, increased risk of incipient TB. Rec85a, Rec85b and Rv1284 are also of interest to study further in this context.
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  • Andreasson, Anna Nixon, et al. (författare)
  • Inflammation and positive affect are associated with subjective health in women of the general population
  • 2013
  • Ingår i: Journal of Health Psychology. - 1359-1053 .- 1461-7277. ; 18:3, s. 311-320
  • Tidskriftsartikel (refereegranskat)abstract
    • Poor subjective health has been associated with higher levels of inflammatory cytokines. We investigated whether such an association would apply to women of the general population. Levels of cytokines, affect and subjective health were assessed in 347 women of the general population aged 45 to 90 years. Higher levels of interleukin-6 were associated with poor subjective health, especially in participants over 65 years of age. Positive affect was a more robust determinant of subjective health than negative affect. The presence of low-grade inflammation and absence of positive affect, rather than presence of negative affect, may be important determinants of subjective health.
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