المؤلفون: Bull, Caroline J., Hazelwood, Emma, Legge, Danny N., Corbin, Laura J., Richardson, Tom G., Lee, Matthew, Yarmolinsky, James, Smith-Byrne, Karl, Hughes, David A., Johansson, Mattias, Peters, Ulrike, Berndt, Sonja I., Brenner, Hermann, Burnett-Hartman, Andrea, Cheng, Iona, Kweon, Sun-Seog, Le Marchand, Loic, Li, Li, Newcomb, Polly A., Pearlman, Rachel, McConnachie, Alex, Welsh, Paul, Taylor, Roy, Lean, Mike E.J., Sattar, Naveed, Murphy, Neil, Gunter, Marc J., Timpson, Nicholas J., Vincent, Emma E.

الوصف: Background Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm ...

وصف الملف: text

العلاقة: https://eprints.gla.ac.uk/319601/1/319601.pdfTest; Bull, C. J. et al. (2024) Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes. EBioMedicine , 100, 104977. (doi:10.1016/j.ebiom.2024.104977 ) (PMID:38290287) (PMCID:PMC10844806)

الإتاحة: https://doi.org/10.1016/j.ebiom.2024.104977Test
https://eprints.gla.ac.uk/319601Test/
https://eprints.gla.ac.uk/319601/1/319601.pdfTest

المؤلفون: Corbin, Laura J, Hughes, David A, Bull, Caroline J, Vincent, Emma E, Smith, Madeleine L, McConnachie, Alex, Messow, Claudia-Martina, Welsh, Paul, Taylor, Roy, Lean, Mike E.J., Sattar, Naveed, Timpson, Nicholas John

المصدر: Corbin , L J , Hughes , D A , Bull , C J , Vincent , E E , Smith , M L , McConnachie , A , Messow , C-M , Welsh , P , Taylor , R , Lean , M E J , Sattar , N & Timpson , N J 2024 , ' The metabolomic signature of weight loss and remission in the Diabetes Remission Clinical Trial (DiRECT) ' , Diabetologia , vol. 67 , no. 1 , pp. 74-87 . https://doi.org/10.1007/s00125-023-06019-xTest

الوصف: Aims/hypothesis High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes. Methods We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted 1H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels. Results Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission. Conclusions/interpretation We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes.

العلاقة: https://research-information.bris.ac.uk/en/publications/ea4f03c4-e70c-4152-b0a6-d76c0c3d2633Test

الإتاحة: https://doi.org/10.1007/s00125-023-06019-xTest
https://hdl.handle.net/1983/ea4f03c4-e70c-4152-b0a6-d76c0c3d2633Test
https://research-information.bris.ac.uk/en/publications/ea4f03c4-e70c-4152-b0a6-d76c0c3d2633Test

المؤلفون: Bull, Caroline J, Hazelwood, Emma, Legge, Danny N, Corbin, Laura J, Richardson, Tom G, Lee, Matthew, Yarmolinsky, James, Smith-Byrne, Karl, Hughes, David A, Johansson, Mattias, Peters, Ulrike, Berndt, Sonja I, Brenner, Hermann, Burnett-Hartman, Andrea, Cheng, Iona, Kweon, Sun-Seog, Le Marchand, Loic, Li, Li, Newcomb, Polly A, Pearlman, Rachel, McConnachie, Alex, Welsh, Paul, Taylor, Roy, Lean, Mike E. J., Sattar, Naveed, Murphy, Neil, Gunter, Marc, Timpson, Nicholas John, Vincent, Emma E

المصدر: Bull , C J , Hazelwood , E , Legge , D N , Corbin , L J , Richardson , T G , Lee , M , Yarmolinsky , J , Smith-Byrne , K , Hughes , D A , Johansson , M , Peters , U , Berndt , S I , Brenner , H , Burnett-Hartman , A , Cheng , I , Kweon , S-S , Le Marchand , L , Li , L , Newcomb , P A , Pearlman , R , McConnachie , A , Welsh , P , Taylor , R ....

مصطلحات موضوعية: /dk/atira/pure/core/keywords/icep, name=ICEP

الوصف: Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm ...

العلاقة: https://research-information.bris.ac.uk/en/publications/cee7fdcb-1a02-4d7f-a168-ca060f0193b9Test

الإتاحة: https://doi.org/10.1016/j.ebiom.2024.104977Test
https://hdl.handle.net/1983/cee7fdcb-1a02-4d7f-a168-ca060f0193b9Test
https://research-information.bris.ac.uk/en/publications/cee7fdcb-1a02-4d7f-a168-ca060f0193b9Test
https://authors.elsevier.com/sd/article/S2352396424000124Test

المؤلفون: Constantinescu, Andrei, Hughes, David A, Bull, Caroline J, Fleming, Kathryn M, Mitchell, Ruth E, Zheng, Jie, Kar, Siddhartha, Timpson, Nicholas John, Amulic, Borko, Vincent, Emma E

المصدر: Constantinescu , A , Hughes , D A , Bull , C J , Fleming , K M , Mitchell , R E , Zheng , J , Kar , S , Timpson , N J , Amulic , B & Vincent , E E 2024 , ' A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitate studies of malaria pathogenesis ' , Human Genomics , vol. 18 , no. 26 , 26 . https://doi.org/10.1186/s40246-024-00585-wTest

مصطلحات موضوعية: /dk/atira/pure/core/keywords/icep, name=ICEP

الوصف: Background 'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056). Results We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r2 = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null. Conclusion Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link ...

العلاقة: https://research-information.bris.ac.uk/en/publications/e8979da3-6223-4ddb-8da0-7e63cdf0631dTest

الإتاحة: https://doi.org/10.1186/s40246-024-00585-wTest
https://hdl.handle.net/1983/e8979da3-6223-4ddb-8da0-7e63cdf0631dTest
https://research-information.bris.ac.uk/en/publications/e8979da3-6223-4ddb-8da0-7e63cdf0631dTest

المؤلفون: Farook, M. Rufaik, Croxford, Zack, Morgan, Steffan, Horlock, Anthony D., Holt, Amy K., Rees, April, Jenkins, Benjamin J., Tse, Carmen, Stanton, Emma, Davies, D. Mark, Thornton, Catherine A., Jones, Nicholas, Sheldon, I. Martin, Vincent, Emma E., Cronin, James G.

المصدر: Molecular Metabolism ; volume 81, page 101900 ; ISSN 2212-8778

مصطلحات موضوعية: Cell Biology, Molecular Biology

الإتاحة: https://doi.org/10.1016/j.molmet.2024.101900Test
https://api.elsevier.com/content/article/PII:S2212877824000310?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2212877824000310?httpAccept=text/plainTest

المؤلفون: Murphy, Neil, Song, Mingyang, Papadimitriou, Nikos, Carreras-Torres, Robert, Langenberg, Claudia, Martin, Richard M, Tsilidis, Konstantinos K, Barroso, Inês, Chen, Ji, Frayling, Timothy M, Bull, Caroline J, Vincent, Emma E, Cotterchio, Michelle, Gruber, Stephen B, Pai, Rish K, Newcomb, Polly A, Perez-Cornago, Aurora, Van Duijnhoven, Franzel J. B, van Guelpen, Bethany, Vodicka, Pavel, Wolk, Alicja, Wu, Anna H., Peters, Ulrike, Chan, Andrew T, Gunter, Marc J

المصدر: Journal of the National Cancer Institute. 114(5):740-752

الوصف: Background: Glycemic traits - such as hyperinsulinemia, hyperglycemia, and type 2 diabetes - have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. Methods: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). Results: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. Conclusions: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.

وصف الملف: print

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-203141Test
https://doi.org/10.1093/jnci/djac011Test

المؤلفون: Holt, Amy K., Najumudeen, Arafath K., Collard, Tracey J., Li, Hao, Millett, Laura M., Hoskin, Ashley J., Legge, Danny N., Mortensson, Eleanor M. H., Flanagan, Dustin J., Jones, Nicholas, Kollareddy, Madhu, Timms, Penny, Hitchings, Matthew D., Cronin, James, Sansom, Owen J., Williams, Ann C., Vincent, Emma E.

المساهمون: Institute of Biotechnology, Kidney development, Helsinki Institute of Life Science HiLIFE

مصطلحات موضوعية: Aspirin, Cb-839, Colorectal cancer, Glutaminase, Metabolic reprogramming, Metabolism, 1182 Biochemistry, cell and molecular biology

الوصف: BackgroundTo support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.MethodsWe generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.ResultsWe show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.ConclusionsTogether, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: AKH and AJH were supported by the James Tudor Foundation; AKH, AJH and EMHM were supported by John and Bridget Maynard; and PT was supported by a PhD studentship from Bowel & Cancer Research. AKH, AJH, EMHM and PT were also supported by the John James Bristol Foundation. DF, TJC, OJS and ACW by an MRC Research Grant (MR/R017247/1). EEV and DNL are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). EEV and TJC are supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). AKN was supported by Cancer Research UK (CRUK) Beatson Institute core funding (A17196, A31287)-awarded to OJS. OJS was supported by CRUK grants (A21139, A12481, A17196 and A31287) and ERC Starting grant (311301). LMM is supported by a CRUK Scotland Centre Grant (CTRQQR-2021\100006).; Holt , A K , Najumudeen , A K , Collard , T J , Li , H , Millett , L M , Hoskin , A J , Legge , D N , Mortensson , E M H , Flanagan , D J , Jones , N , Kollareddy , M , Timms , P , Hitchings , M D , Cronin , J , Sansom , O J , Williams , A C & Vincent , E E 2023 , ' Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition ' , Cancer & Metabolism , vol. 11 , 18 . https://doi.org/10.1186/s40170-023-00318-yTest; 79183b88-6bce-46f8-be9f-33f80fb83f77; http://hdl.handle.net/10138/568723Test; 001097431700001

الإتاحة: http://hdl.handle.net/10138/568723Test

المؤلفون: Jenkins, Benjamin J, Blagih, Julianna, Ponce-Garcia, Fernando M, Canavan, Mary, Gudgeon, Nancy, Eastham, Simon, Hill, David, Hanlon, Megan M, Ma, Eric H, Bishop, Emma L, Rees, April, Cronin, James G, Jury, Elizabeth C, Dimeloe, Sarah K, Veale, Douglas J, Thornton, Catherine A, Vousden, Karen H, Finlay, David K, Fearon, Ursula, Jones, Gareth W, Sinclair, Linda V, Vincent, Emma E, Jones, Nicholas

المصدر: Cell Metabolism (2023) (In press).

مصطلحات موضوعية: CD4 T cell, T cell, autoimmunity, canagliflozin, gliflozins, human, immunometabolism

الوصف: Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10171393/1/1-s2.0-S155041312300178X-main.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10171393Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10171393/1/1-s2.0-S155041312300178X-main.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10171393Test/

المؤلفون: Gormley, Mark, Dudding, Tom, Thomas, Steven J, Tyrrell, Jessica, Ness, Andrew R, Pring, Miranda, Legge, Danny, Smith, George Davey, Richmond, Rebecca C, Vincent, Emma E, Bull, Caroline

المصدر: Gormley , M , Dudding , T , Thomas , S J , Tyrrell , J , Ness , A R , Pring , M , Legge , D , Smith , G D , Richmond , R C , Vincent , E E & Bull , C 2023 , ' Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization ' , eLife , vol. 12 , e82674 . https://doi.org/10.7554/eLife.82674Test

مصطلحات موضوعية: /dk/atira/pure/core/keywords/population_health_SRI, name=Bristol Population Health Science Institute, /dk/atira/pure/core/keywords/icep, name=ICEP

الوصف: A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted (IVW) method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data was taken from the largest available GWAS of 6,034 oral and oropharyngeal cases, with 6,585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (OR IVW = 0.89, 95%CI 0.72-1.09, p = 0.26 per 1 SD in BMI (4.81 kg/m2)) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including type 2 diabetes and hypertension.

العلاقة: https://research-information.bris.ac.uk/en/publications/f9d2179d-8fd9-4148-8178-7c4eee776eaeTest

الإتاحة: https://doi.org/10.7554/eLife.82674Test
https://hdl.handle.net/1983/f9d2179d-8fd9-4148-8178-7c4eee776eaeTest
https://research-information.bris.ac.uk/en/publications/f9d2179d-8fd9-4148-8178-7c4eee776eaeTest

المؤلفون: Bull, Caroline J, Hazelwood, Emma, Bell, Joshua A, Tan, Y, Constantinescu, Andrei, Borges, Maria C, Legge, Danny N, Burrows, Kimberley, Huyghe, Jeroen R, Brenner, Hermann, Castellví-Bel, Sergi, Chan, Andrew T., Kweon, Sun-Seog, Le Marchand, Loïc, Li, Li, Cheng, Iona, Rish, Pai K., Figueiredo, Jane C., Murphy, Neil, Gunter , Marc J., Timpson, Nicholas John, Vincent, Emma E

المصدر: Bull , C J , Hazelwood , E , Bell , J A , Tan , Y , Constantinescu , A , Borges , M C , Legge , D N , Burrows , K , Huyghe , J R , Brenner , H , Castellví-Bel , S , Chan , A T , Kweon , S-S , Le Marchand , L , Li , L , Cheng , I , Rish , P K , Figueiredo , J C , Murphy , N , Gunter , M J , Timpson , N J & Vincent , E E ....

مصطلحات موضوعية: /dk/atira/pure/core/keywords/icep, name=ICEP

الوصف: Background: Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods: To investigate whether changes in circulating metabolites characterize the early stages of colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y. Results: The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions: These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development. Funding: This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced ...

العلاقة: https://research-information.bris.ac.uk/en/publications/6d9211bc-84c0-40e7-953e-b26cdb914d07Test

الإتاحة: https://doi.org/10.7554/eLife.87894Test
https://hdl.handle.net/1983/6d9211bc-84c0-40e7-953e-b26cdb914d07Test
https://research-information.bris.ac.uk/en/publications/6d9211bc-84c0-40e7-953e-b26cdb914d07Test
https://elifesciences.org/articles/87894Test