Citations

Abstract Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells—a highly dynamic lymphocyte subtype—undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified 6 genes—FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258—with strong evidence for a causal role in CRC development (FDR-P < 0.05; colocalisation H4 > 0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.

Abstract Introduction There is convincing evidence that overall adiposity increases the risks of several cancers. Whether the distribution of adiposity plays a similar role is unclear. Methods We used 2-sample Mendelian randomization (MR) to examine causal relationships of 5 adiposity distribution traits (abdominal subcutaneous adipose tissue (ASAT); visceral adipose tissue (VAT); gluteofemoral adipose tissue (GFAT); liver fat; and pancreas fat) with the risks of 12 obesity-related cancers (endometrial, ovarian, breast, colorectal, pancreas, multiple myeloma, liver, kidney (renal cell), thyroid, gallbladder, esophageal adenocarcinoma, and meningioma). Results Sample size across all genome-wide association studies (GWAS) ranged from 8407 to 728 896 (median: 57 249). We found evidence that higher genetically predicted ASAT increased the risks of endometrial cancer, liver cancer, and esophageal adenocarcinoma (odds ratios (OR) and 95% confidence intervals (CI) per standard deviation (SD) higher ASAT = 1.79 (1.18 to 2.71), 3.83 (1.39 to 10.53), and 2.34 (1.15 to 4.78), respectively). Conversely, we found evidence that higher genetically predicted GFAT decreased the risks of breast cancer and meningioma (ORs and 95% CIs per SD higher genetically predicted GFAT = 0.77 (0.62 to 0.97) and 0.53 (0.32 to 0.90), respectively). We also found evidence for an effect of higher genetically predicted VAT and liver fat on increased liver cancer risk (ORs and 95% CIs per SD higher genetically predicted adiposity trait = 4.29 (1.41 to 13.07) and 4.09 (2.29 to 7.28), respectively). Discussion Our analyses provide novel insights into the relationship between adiposity distribution and cancer risk. These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.

Abstract Background & Aims Pregnancy can be a complex and risk-filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process was used when sufficient published data were available and the RAND (Research and Development) process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

Abstract Background: Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and colorectal cancer risk overall and by sex, cancer subsite, and age at diagnosis. Methods: Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for colorectal cancer risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied. Results: We found no evidence for an association of genetically predicted plasma total ghrelin levels and colorectal cancer risk (0.95, 95% confidence interval, 0.81–1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset colorectal cancer. Conclusions: Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite–stratified colorectal cancer risk. Impact: This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with colorectal cancer risk.

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 Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/ .

Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined 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=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. 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 58y) 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. 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.

Abstract Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual‐level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse‐variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1‐SD increase: 0.88, 95% CI: 0.78‐0.99, P = .04; OR: 0.93, 95% CI: 0.88‐0.98, P = .01]. The protective effect of eosinophils remained [OR per 1‐SD increase: 0.88, 95% CI: 0.80‐0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76‐0.93, P = 6.70e‐4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1‐SD increase: 0.96, 95% CI: 0.93‐0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93‐0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

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 Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/ .

Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined 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=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. 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 58y) 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. 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.