| 1. |
|
|
| 2. |
- Sampson, Joshua N., et al.
(författare)
-
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
- Jevnikar, Z., et al.
(författare)
-
Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
- 2019
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 143:2, s. 577-590
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
|
|
| 16. |
|
|
| 17. |
- Jorgensen, J. K., et al.
(författare)
-
The ALMA-PILS survey: isotopic composition of oxygen-containing complex organic molecules toward IRAS 16293-2422B
- 2018
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 620
-
Tidskriftsartikel (refereegranskat)abstract
- Context. One of the important questions of astrochemistry is how complex organic molecules, including potential prebiotic species, are formed in the envelopes around embedded protostars. The abundances of minor isotopologues of a molecule, in particular the D- and C-13-bearing variants, are sensitive to the densities, temperatures and timescales characteristic of the environment in which they form, and can therefore provide important constraints on the formation routes and conditions of individual species. Aims. The aim of this paper is to systematically survey the deuteration and the C-13 content of a variety of oxygen-bearing complex organic molecules on solar system scales toward the "B component" of the protostellar binary IRAS16293-2422. Methods. We have used the data from an unbiased molecular line survey of the protostellar binary IRAS16293-2422 between 329 and 363 GHz from the Atacama Large Millimeter/submillimeter Array (ALMA). The data probe scales of 60 AU (diameter) where most of the organic molecules are expected to have sublimated off dust grains and be present in the gas phase. The deuterated and C-13 isotopic species of ketene, acetaldehyde and formic acid, as well as deuterated ethanol, are detected unambiguously for the first time in the interstellar medium. These species are analysed together with the C-13 isotopic species of ethanol, dimethyl ether and methyl formate along with mono-deuterated methanol, dimethyl ether and methyl formate. Results. The complex organic molecules can be divided into two groups with one group, the simpler species, showing a D/H ratio of approximate to 2% and the other, the more complex species, D/H ratios of 4-8%. This division may reflect the formation time of each species in the ices before or during warm-up/infall of material through the protostellar envelope. No significant differences are seen in the deuteration of different functional groups for individual species, possibly a result of the short timescale for infall through the innermost warm regions where exchange reactions between different species may be taking place. The species show differences in excitation temperatures between 125 and 300 K. This likely reflects the binding energies of the individual species, in good agreement with what has previously been found for high-mass sources. For dimethyl ether, the C-12/C-13 ratio is found to be lower by up to a factor of 2 compared to typical ISM values similar to what has previously been inferred for glycolaldehyde. Tentative identifications suggest that the same may apply for C-13 isotopologues of methyl formate and ethanol. If confirmed, this may be a clue to their formation at the late prestellar or early protostellar phases with an enhancement of the available C-13 relative to C-12 related to small differences in binding energies for CO isotopologues or the impact of FUV irradiation by the central protostar. Conclusions. The results point to the importance of ice surface chemistry for the formation of these complex organic molecules at different stages in the evolution of embedded protostars and demonstrate the use of accurate isotope measurements for understanding the history of individual species.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
