| 1. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 2. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 3. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 4. |
- Wu, Lang, et al.
(författare)
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Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk : A Transcriptome-Wide Association Study in over 140,000 European Descendants
- 2019
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:13, s. 3192-3204
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 x 10(-6), a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 x 10(-6) after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. Significance: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.
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| 5. |
- Adams, Charleen, et al.
(författare)
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Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study
- 2019
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:1, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
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| 6. |
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| 7. |
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| 8. |
- Bombarda, F., et al.
(författare)
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Runaway electron beam control
- 2019
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 1361-6587 .- 0741-3335. ; 61:1
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Brevini, T, et al.
(författare)
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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7950, s. 134-
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Tidskriftsartikel (refereegranskat)abstract
- Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
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| 10. |
- Clements-Croome, Derek, et al.
(författare)
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Research Roadmap for Intelligent and Responsive Buildings
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Intelligence has three parts cognitive, emotional and practical. A building needs to reflect this. So an intelligent building will responsive to people in terms of not only being functional but to the human senses besides serving a community in the location. It will be resource effective in terms of energy , water and waste with low pollution. It will be smart in terms of technology selected to enable the systems to respond effectively but also make them easier for people to use. Today there is a focus on health and wellbeing and so intelligent buildings must produce a healing environment. Buildings need to be functional and practical but also expressive. Equally important is the infrastructure that services buildings and the people moving between them.
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| 11. |
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| 12. |
- Dadaev, T, et al.
(författare)
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Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2256-
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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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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Finn, Robert D., et al.
(författare)
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Pfam : the protein families database
- 2014
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 42:D1, s. d222-D230
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Tidskriftsartikel (refereegranskat)abstract
- Pfam, available via servers in the UK (http://pfam.sanger.ac.uk/) and the USA (http://pfam.janelia.org/), is a widely used database of protein families, containing 14 831 manually curated entries in the current release, version 27.0. Since the last update article 2 years ago, we have generated 1182 new families and maintained sequence coverage of the UniProt Knowledgebase (UniProtKB) at nearly 80%, despite a 50% increase in the size of the underlying sequence database. Since our 2012 article describing Pfam, we have also undertaken a comprehensive review of the features that are provided by Pfam over and above the basic family data. For each feature, we determined the relevance, computational burden, usage statistics and the functionality of the feature in a website context. As a consequence of this review, we have removed some features, enhanced others and developed new ones to meet the changing demands of computational biology. Here, we describe the changes to Pfam content. Notably, we now provide family alignments based on four different representative proteome sequence data sets and a new interactive DNA search interface. We also discuss the mapping between Pfam and known 3D structures.
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| 17. |
- Garber, John J., et al.
(författare)
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Increasing incidence of eosinophilic esophagitis in Sweden : a nationwide population study
- 2022
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Ingår i: Esophagus. - : Springer. - 1612-9059 .- 1612-9067. ; 19:4, s. 535-541
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Tidskriftsartikel (refereegranskat)abstract
- Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus associated with dysphagia and esophageal fibrosis. The incidence of EoE is not precisely known, and significant heterogeneity in study design and disease definition have led to widely variable estimates. Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study we performed a nationwide population-based study to estimate the incidence and temporal patterns of biopsy-verified EoE.Methods: Between October 2015 and April 2017, we contacted all pathology departments in Sweden (n = 28) to obtain biopsy report data on EoE. To assure a high degree of completeness, we restricted the study to 2004-2015. We then calculated age-specific and age-standardized incidence rates.Results: We identified 1412 incident EoE cases between 2004-2015. The overall age-standardized incidence rates of EoE in Sweden was 1.22 per 100,000 person-years. During the study period, there was a significant increase of 33% [95%CI = 31-36%] (P < 0.001) per year in EoE incidence, and in the last 3 years of follow-up (2013-2015) the incidence was 2.79 per 100,000 person-years. This corresponds to a lifetime risk of biopsy-verified EoE for men of 0.33% (1 in 295 men) and for women 0.12% (1 in 813 women). We observed an early peak of EoE disgnosed at age 15-19 years for both males and females, and a second peak in the late 30 s for males, and early 40 s for females. We noted a 3:1 male-to-female predominance, which did not significantly vary over time.Conclusions: EoE seems to be increasing in Sweden, with an overall age-standardized incidence of EoE of 1.22 per 100,000 person-years in the last decade.
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| 18. |
- Gilbert, Benjamin, et al.
(författare)
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A bioenergetic framework for the temperature dependence of trophic interactions
- 2014
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 17:8, s. 902-914
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Tidskriftsartikel (refereegranskat)abstract
- Changing temperature can substantially shift ecological communities by altering the strength and stability of trophic interactions. Because many ecological rates are constrained by temperature, new approaches are required to understand how simultaneous changes in multiple rates alter the relative performance of species and their trophic interactions. We develop an energetic approach to identify the relationship between biomass fluxes and standing biomass across trophic levels. Our approach links ecological rates and trophic dynamics to measure temperature-dependent changes to the strength of trophic interactions and determine how these changes alter food web stability. It accomplishes this by using biomass as a common energetic currency and isolating three temperature-dependent processes that are common to all consumer-resource interactions: biomass accumulation of the resource, resource consumption and consumer mortality. Using this framework, we clarify when and how temperature alters consumer to resource biomass ratios, equilibrium resilience, consumer variability, extinction risk and transient vs. equilibrium dynamics. Finally, we characterise key asymmetries in species responses to temperature that produce these distinct dynamic behaviours and identify when they are likely to emerge. Overall, our framework provides a mechanistic and more unified understanding of the temperature dependence of trophic dynamics in terms of ecological rates, biomass ratios and stability.
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| 19. |
- Gusev, A, et al.
(författare)
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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 10979-
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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.
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| 20. |
- Jalloh, Mohamed F., et al.
(författare)
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Evidence of behaviour change during an Ebola virus disease outbreak, Sierra Leone
- 2020
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Ingår i: Bulletin of the World Health Organization. - : World Health Organization. - 0042-9686 .- 1564-0604. ; 98:5, s. 330-340
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate changes in Ebola-related knowledge, attitudes and prevention practices during the Sierra Leone outbreak between 2014 and 2015.Methods Four cluster surveys were conducted: two before the outbreak peak (3499 participants) and two after (7104 participants). We assessed the effect of temporal and geographical factors on 16 knowledge, attitude and practice outcomes.Findings Fourteen of 16 knowledge, attitude and prevention practice outcomes improved across all regions from before to after the outbreak peak. The proportion of respondents willing to: (i) welcome Ebola survivors back into the community increased from 60.0% to 89.4% (adjusted odds ratio, aOR: 6.0; 95% confidence interval, CI: 3.9–9.1); and (ii) wait for a burial team following a relative’s death increased from 86.0% to 95.9% (aOR: 4.4; 95% CI: 3.2–6.0). The proportion avoiding unsafe traditional burials increased from 27.3% to 48.2% (aOR: 3.1; 95% CI: 2.4–4.2) and the proportion believing spiritual healers can treat Ebola decreased from 15.9% to 5.0% (aOR: 0.2; 95% CI: 0.1–0.3). The likelihood respondents would wait for burial teams increased more in high-transmission (aOR: 6.2; 95% CI: 4.2–9.1) than low-transmission (aOR: 2.3; 95% CI: 1.4–3.8) regions. Self-reported avoidance of physical contact with corpses increased in high but not low-transmission regions, aOR: 1.9 (95% CI: 1.4–2.5) and aOR: 0.8 (95% CI: 0.6–1.2), respectively.Conclusion Ebola knowledge, attitudes and prevention practices improved during the Sierra Leone outbreak, especially in high-transmission regions. Behaviourally-targeted community engagement should be prioritized early during outbreaks.
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| 21. |
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| 22. |
- Jiang, X., et al.
(författare)
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Shared heritability and functional enrichment across six solid cancers
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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| 23. |
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| 25. |
- Leach, Susannah, 1983, et al.
(författare)
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The Adjuvant Double Mutant Escherichia coli Heat Labile Toxin Enhances IL-17A Production in Human T Cells Specific for Bacterial Vaccine Antigens
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- The strong adjuvant activity and low enterotoxicity of the novel mucosal adjuvant double mutant Escherichia coli heat labile toxin, LT(R192G/L211A) or dmLT, demonstrated in mice, makes this molecule a promising adjuvant candidate. However, little is known about the mechanisms responsible for the adjuvant effect of dmLT or whether dmLT also has an adjuvant function in humans. We investigated the effect of dmLT on human T cell responses to different bacterial vaccine antigens: the mycobacterial purified protein derivative (PPD) antigen, tested in individuals previously vaccinated with Bacillus Calmette-Gue ́rin, the LT binding subunit (LTB), evaluated in subjects immunised with oral inactivated whole cell vaccines against enterotoxigenic Escherichia coli, and Streptococcus pneumoniae whole cell vaccine antigens, tested in subjects naturally exposed to pneumococci. We found that dmLT enhanced the production of IL-17A by peripheral blood mononuclear cells in response to all antigens tested. dmLT had comparable effects on IL-17A responses to PPD as the single mutant LT(R192G) adjuvant, which has demonstrated clinical adjuvant activity in humans. Neutralisation of IL-1b and IL-23, but not IL-6, suppressed the IL-17A-enhancing effect of dmLT. Furthermore, CD4+ T cells produced higher levels of IL-17A when stimulated with monocytes pulsed with PPD and dmLT compared to PPD alone, supporting an important role of antigen presenting cells in enhancing IL-17A responses. dmLT also potentiated mitogen-induced IL-17A and IL-13 production. However, dmLT had variable influences on IFN-c responses to the different stimuli tested. Our demonstration of a potent ability of dmLT to enhance human Th17 type T cell responses to bacterial vaccine antigens encourages further evaluation of the adjuvant function of dmLT in humans.
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