Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients.

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1  = 1.53, 95% CI: 1.04-2.25, Ptrend  = .002) and all-cause (HRQ5 vs Q1  = 1.62, 95% CI: 1.16-2.26, Ptrend  < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon  = 1.02, 95% CI: 0.74-1.42; HRdistal colon  = 1.51, 95% CI: 1.20-1.91; Peffect modification  = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.

Associations of intakes of total protein, protein from dairy sources, and dietary calcium with risks of colorectal, breast, and prostate cancer: a prospective analysis in UK Biobank.

BACKGROUND: Evidence concerning intakes of protein or sources of dairy protein and risks of colorectal, breast, and prostate cancers is inconclusive. METHODS: Using a subsample of UK Biobank participants who completed ≥2 (maximum of 5) 24-h dietary assessments, we estimated intakes of total protein, protein from total dairy products, milk, and cheese, and dietary calcium in 114,217 participants. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using multivariable-adjusted Cox regression. RESULTS: After a median of 9.4 years of follow-up, 1193 colorectal, 2024 female breast, and 2422 prostate cancer cases were identified. There were inverse associations of total dairy protein, protein from milk, and dietary calcium intakes with colorectal cancer incidence (HRQ4 vs Q1:0.80, 95% CI: 0.67-0.94; 0.79, 0.67-0.94; 0.71, 0.58-0.86, respectively). We also observed positive associations of milk protein and dietary calcium with prostate cancer risk (HRQ4 vs Q1:1.12, 1.00-1.26 and 1.16, 1.01-1.33, respectively). No significant associations were observed between intake of dairy protein and breast cancer risk. When insulin-like growth factor-I concentrations measured at recruitment were added to the multivariable-adjusted models, associations remained largely unchanged. Analyses were also similar when looking at total grams of dairy products, milk, and cheese. CONCLUSION: Further research is needed to understand the mechanisms underlying the relationships of dairy products with cancer risk and the potential roles of dietary protein and calcium.

Body shape phenotypes of multiple anthropometric traits and cancer risk: a multi-national cohort study.

BACKGROUND: Classical anthropometric traits may fail to fully represent the relationship of weight, adiposity, and height with cancer risk. We investigated the associations of body shape phenotypes with the risk of overall and site-specific cancers. METHODS: We derived four distinct body shape phenotypes from principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). The study included 340,152 men and women from 9 European countries, aged mostly 35-65 years at recruitment (1990-2000) in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: After a median follow-up of 15.3 years, 47,110 incident cancer cases were recorded. PC1 (overall adiposity) was positively associated with the risk of overall cancer, with a HR per 1 standard deviation (SD) increment equal to 1.07 (95% confidence interval 1.05 to 1.08). Positive associations were observed with 10 cancer types, with HRs (per 1 SD) ranging from 1.36 (1.30-1.42) for endometrial cancer to 1.08 (1.03-1.13) for rectal cancer. PC2 (tall stature with low WHR) was positively associated with the risk of overall cancer (1.03; 1.02-1.04) and five cancer types which were not associated with PC1. PC3 (tall stature with high WHR) was positively associated with the risk of overall cancer (1.04; 1.03-1.05) and 12 cancer types. PC4 (high BMI and weight with low WC and HC) was not associated with overall risk of cancer (1.00; 0.99-1.01). CONCLUSIONS: In this multi-national study, distinct body shape phenotypes were positively associated with the incidence of 17 different cancers and overall cancer.

Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation Into Cancer and Nutrition.

INTRODUCTION: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort. METHODS: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile. DISCUSSION: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

Associations between types and sources of dietary carbohydrates and liver fat: a UK Biobank study.

BACKGROUND AND AIMS: Excess energy intake can lead to metabolic dysfunction-associated steatotic liver disease (MASLD), but the relationship between dietary carbohydrate intake and liver fat content remains unclear. This study aimed to examine the associations between types and sources of dietary carbohydrates and liver fat content. METHODS: UK Biobank participants with no pre-existing diabetes, liver disease or cardiovascular disease reported dietary intake of types and sources of carbohydrates (total carbohydrates, free sugars, non-free sugars, starch from whole grains, starch from refined grains, and fibre) on at least two 24-h dietary assessments. In cross-sectional analyses, (n = 22,973), odds ratios (OR) of high liver fat content (defined as a score of ≥ 36 in the hepatic steatosis index) by quintiles of carbohydrate intakes were estimated using multivariable logistic regression models. In prospective analyses, a second sample (n = 9268) had liver proton density fat fraction (PDFF) measured by magnetic resonance imaging (2014-2020). Multivariable linear regression models estimated geometric means of PDFF (%) by quintiles of carbohydrate intakes. Models were adjusted for demographic and lifestyle confounders, including total energy intake. RESULTS: In the cross-sectional analyses, 6894 cases of high liver fat content were identified. Inverse associations between intakes of fibre (OR of highest vs. lowest quintile 0.46 [95% CI: 0.41-0.52]), non-free sugars (0.63 [0.57-0.70]) and starch from whole grains (0.52 [0.47-0.57]) with liver fat were observed. There were positive associations between starch from refined grains and liver fat (1.33 [1.21-1.46]), but no association with free sugars (p=0.61). In prospective analyses, inverse associations with PDFF (%) were observed for intakes of fibre (- 0.48 geometric mean difference between highest and lowest quintile of intake [- 0.60 to - 0.35]), non-free sugars (- 0.37 [- 0.49 to - 0.25]) and starch from whole grains (- 0.31 [- 0.42 to - 0.19]). Free sugars, but not starch from refined grains, were positively associated with PDFF (0.17 [0.05 to 0.28]). CONCLUSION: This study suggests that different carbohydrate types and sources have varying associations with liver fat, which may be important for MASLD prevention. Non-free sugars, fibre, and starch from whole grains could be protective, while associations with free sugars and starch from refined grains are less clear.

Associations between types and sources of dietary carbohydrates and cardiovascular disease risk: a prospective cohort study of UK Biobank participants.

BACKGROUND: Recent studies have reported that the associations between dietary carbohydrates and cardiovascular disease (CVD) may depend on the quality, rather than the quantity, of carbohydrates consumed. This study aimed to assess the associations between types and sources of dietary carbohydrates and CVD incidence. A secondary aim was to examine the associations of carbohydrate intakes with triglycerides within lipoprotein subclasses. METHODS: A total of 110,497 UK Biobank participants with ≥ two (maximum five) 24-h dietary assessments who were free from CVD and diabetes at baseline were included. Multivariable-adjusted Cox regressions were used to estimate risks of incident total CVD (4188 cases), ischaemic heart disease (IHD; 3138) and stroke (1124) by carbohydrate intakes over a median follow-up time of 9.4 years, and the effect of modelled dietary substitutions. The associations of carbohydrate intakes with plasma triglycerides within lipoprotein subclasses as measured by nuclear magnetic resonance (NMR) spectroscopy were examined in 26,095 participants with baseline NMR spectroscopy measurements. RESULTS: Total carbohydrate intake was not associated with CVD outcomes. Free sugar intake was positively associated with total CVD (HR; 95% CI per 5% of energy, 1.07;1.03-1.10), IHD (1.06;1.02-1.10), and stroke (1.10;1.04-1.17). Fibre intake was inversely associated with total CVD (HR; 95% CI per 5 g/d, 0.96;0.93-0.99). Modelled isoenergetic substitution of 5% of energy from refined grain starch with wholegrain starch was inversely associated with total CVD (0.94;0.91-0.98) and IHD (0.94;0.90-0.98), and substitution of free sugars with non-free sugars was inversely associated with total CVD (0.95;0.92-0.98) and stroke (0.91;0.86-0.97). Free sugar intake was positively associated with triglycerides within all lipoproteins. CONCLUSIONS: Higher free sugar intake was associated with higher CVD incidence and higher triglyceride concentrations within all lipoproteins. Higher fibre intake and replacement of refined grain starch and free sugars with wholegrain starch and non-free sugars, respectively, may be protective for incident CVD.

A body shape index (ABSI) is associated inversely with post-menopausal progesterone-receptor-negative breast cancer risk in a large European cohort.

BACKGROUND: Associations of body shape with breast cancer risk, independent of body size, are unclear because waist and hip circumferences are correlated strongly positively with body mass index (BMI). METHODS: We evaluated body shape with the allometric "a body shape index" (ABSI) and hip index (HI), which compare waist and hip circumferences, correspondingly, among individuals with the same weight and height. We examined associations of ABSI, HI, and BMI (per one standard deviation increment) with breast cancer overall, and according to menopausal status at baseline, age at diagnosis, and oestrogen and progesterone receptor status (ER+/-PR+/-) in multivariable Cox proportional hazards models using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. RESULTS: During a mean follow-up of 14.0 years, 9011 incident breast cancers were diagnosed among 218,276 women. Although there was little evidence for association of ABSI with breast cancer overall (hazard ratio HR = 0.984; 95% confidence interval: 0.961-1.007), we found borderline inverse associations for post-menopausal women (HR = 0.971; 0.942-1.000; n = 5268 cases) and breast cancers diagnosed at age ≥ 55 years (HR = 0.976; 0.951-1.002; n = 7043) and clear inverse associations for ER + PR- subtypes (HR = 0.894; 0.822-0.971; n = 726) and ER-PR- subtypes (HR = 0.906; 0.835-0.983 n = 759). There were no material associations with HI. BMI was associated strongly positively with breast cancer overall (HR = 1.074; 1.049-1.098), for post-menopausal women (HR = 1.117; 1.085-1.150), for cancers diagnosed at age ≥ 55 years (HR = 1.104; 1.076-1.132), and for ER + PR + subtypes (HR = 1.122; 1.080-1.165; n = 3101), but not for PR- subtypes. CONCLUSIONS: In the EPIC cohort, abdominal obesity evaluated with ABSI was not associated with breast cancer risk overall but was associated inversely with the risk of post-menopausal PR- breast cancer. Our findings require validation in other cohorts and with a larger number of PR- breast cancer cases.

Associations between food group intakes and circulating insulin-like growth factor-I in the UK Biobank: a cross-sectional analysis.

PURPOSE: Circulating insulin-like growth factor-I (IGF-I) concentrations have been positively associated with risk of several common cancers and inversely associated with risk of bone fractures. Intakes of some foods have been associated with increased circulating IGF-I concentrations; however, evidence remains inconclusive. Our aim was to assess cross-sectional associations of food group intakes with circulating IGF-I concentrations in the UK Biobank. METHODS: At recruitment, the UK Biobank participants reported their intake of commonly consumed foods. From these questions, intakes of total vegetables, fresh fruit, red meat, processed meat, poultry, oily fish, non-oily fish, and cheese were estimated. Serum IGF-I concentrations were measured in blood samples collected at recruitment. After exclusions, a total of 438,453 participants were included in this study. Multivariable linear regression was used to assess the associations of food group intakes with circulating IGF-I concentrations. RESULTS: Compared to never consumers, participants who reported consuming oily fish or non-oily fish ≥ 2 times/week had 1.25 nmol/L (95% confidence interval:1.19-1.31) and 1.16 nmol/L (1.08-1.24) higher IGF-I concentrations, respectively. Participants who reported consuming poultry ≥ 2 times/week had 0.87 nmol/L (0.80-0.94) higher IGF-I concentrations than those who reported never consuming poultry. There were no strong associations between other food groups and IGF-I concentrations. CONCLUSIONS: We found positive associations between oily and non-oily fish intake and circulating IGF-I concentrations. A weaker positive association of IGF-I with poultry intake was also observed. Further research is needed to understand the mechanisms which might explain these associations.

Intakes of major food groups in China and UK: results from 100,000 adults in the China Kadoorie biobank and UK biobank.

PURPOSE: Different populations may exhibit differences in dietary intakes, which may result in heterogeneities in diet-disease associations. We compared intakes of major food groups overall, by sex, and by socio-economic status (SES) (defined as both education and income), between participants in the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). METHODS: Data were from ~ 25,000 CKB participants who completed a validated interviewer-administered computer-based questionnaire (2013-2014) and ~ 74,000 UKB participants who completed ≥ 3 web-based 24-h dietary assessments (2009-2012). Intakes of 12 major food groups and five beverages were harmonized and compared between the cohorts overall, by sex and by SES. Multivariable-adjusted linear regression examined the associations between dietary intakes and body mass index (BMI) in each cohort. RESULTS: CKB participants reported consuming more rice, eggs, vegetables, soya products, and less wheat, other staple foods (other than rice and wheat), fish, poultry, all dairy products, fruit, and beverages compared to UKB participants. Red meat intake was similar in both cohorts. Having a higher SES was generally associated with a higher consumption of foods and beverages in CKB, whereas in UKB dietary intakes differed more by education and income, with a positive association observed for meat and income in both UKB and CKB but an inverse association observed for education in UKB. Associations of dietary intakes with BMI varied between the two cohorts. CONCLUSION: The large differences in dietary intakes and their associations with SES and BMI could provide insight into the interpretation of potentially different diet-disease associations between CKB and UKB.

Cross-sectional associations of dietary patterns characterized by fat type with markers of cardiometabolic health.

BACKGROUND AND AIMS: Individual dietary fats can differentially impact on cardiometabolic health. However, their impact within a dietary pattern is not well understood, and warrants comparison with diet quality scores with a dietary fat focus. The aim of this study was to investigate cross-sectional associations between a posteriori dietary patterns characterized by fat type and cardiometabolic health markers, and compare these with two diet quality scores. METHODS AND RESULTS: UK Biobank adults with ≥two 24-h dietary assessments and data on cardiometabolic health were included (n = 24 553; mean age: 55.9 y). A posteriori dietary patterns (DP1; DP2) were generated through reduced rank regression (response variables: SFA, MUFA, PUFA). Mediterranean Diet Score (MDS) and Dietary Approaches to Stop Hypertension (DASH) dietary patterns were created. Multiple linear regression analyses were used to investigate associations between standardized dietary patterns and cardiometabolic health (total cholesterol, HDL-C, LDL-C and VLDL-C cholesterol, triglycerides, C-reactive protein [CRP], glycated hemoglobin [HbA1c]). DP1, positively correlated with SFAs, MUFAs and PUFAs, characterized by higher nuts, seeds and vegetables intake and lower fruits and low-fat yoghurt intake, was associated with lower HDL-C (ß: -0.07; 95% CI: -0.10, -0.03) and triglycerides (-0.17; -0.23, -0.10) and higher LDL-C (0.07; 0.01,0.12), CRP (0.01; 0.01, 0.03) and HbA1c (0.16; 0.11,0.21). DP2, positively correlated with SFAs, negatively correlated with PUFAs, characterized by higher butter and high-fat cheese intake and lower nuts, seeds and vegetable intake, was associated with higher total cholesterol (0.10; 0.01, 0.21), VLDL-C (0.05; 0.02, 0.07), triglycerides (0.07; 0.01, 0.13), CRP (0.03; 0.02, 0,04) and HbA1c (0.06; 0.01, 0.11). Higher adherence to MDS and DASH was associated with favorable cardiometabolic health markers concentration. CONCLUSIONS: Irrespective of the method used, dietary patterns that encourage healthy fat consumption were associated with favorable cardiometabolic health biomarkers. This study strengthens the evidence for incorporation of dietary fat type into policy and practice guidelines for CVD prevention.

Development and initial qualitative evaluation of a novel school-based nutrition intervention - COOKKIT (Cooking Kit for Kids).

BACKGROUND: Excess weight and an unhealthy diet are risk factors for many cancers, and in high income countries, both are more prevalent among low income families. Dietary interventions targeting primary-school aged children (under 11) can improve healthy eating behaviours, but most are not designed to support the translation of skills learnt in the classroom to the home setting. This paper assessed attitudes and approaches to cooking and eating at home, and the potential to enhance engagement in healthy eating through the COOKKIT intervention. METHODS: COOKKIT is an intervention to deliver weekly cooking classes and supportive materials for low-income families to maintain healthy eating at home. Preliminary qualitative interviews were conducted with teachers and parent-child dyads from a range of primary schools in the UK to explore attitudes, barriers and facilitators for healthy eating and inform the development of COOKKIT. Following implementation, ten children (8-9 y/o) participated in post-intervention focus groups, alongside interviews with teaching staff and parents. RESULTS: Thematic analysis identified five themes under which to discuss the children's experience of food, cooking and the impact of COOKKIT: Involving children in planning and buying food for the family; Engaging children in preparing meals at home; Trying to eat healthy meals together in the midst of busy lives; Role-modelling; and Balancing practicalities, information and engagement when delivering cooking classes. CONCLUSIONS: Results suggest COOKKIT provides engaging and easy to follow in-school resources for children and school staff with take-home kits facilitating continued engagement and reinforcing lessons learned in the home environment. Importantly, participants highlighted the combination of healthy eating information, applied practical skills and low costs could support families to continue following the COOKKIT advice beyond the intervention, suggesting further evaluation of COOKKIT is warranted.

Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling  = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

The relationship between lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study.

BACKGROUND: Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa. METHODS AND FINDINGS: Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)), and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample summary-level Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB, and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis, but adjustment for HDL, TG, and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per standard deviation (SD) = 1.091; 95% CI 1.028 to 1.157; P = 0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per SD = 1.068; 95% CI 1.005 to 1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per SD = 1.078; 95% CI 0.999 to 1.163; P = 0.055) and early age onset PCa (MVMR ORIVW per SD = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilised to minimise the effect of pleiotropy, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings. CONCLUSIONS: We observed that genetically predicted Lp(a) concentrations were associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies.

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC.

BACKGROUND & AIMS: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. METHODS: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. RESULTS: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04-1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04-1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93-0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90-0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90-0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92-0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93-0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. CONCLUSIONS: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.

Adiposity and risk of prostate cancer death: a prospective analysis in UK Biobank and meta-analysis of published studies.

BACKGROUND: The association of adiposity with prostate cancer specific mortality remains unclear. We examined how adiposity relates to fatal prostate cancer and described the cross-sectional associations of commonly used adiposity measurements with adiposity estimated by imaging in UK Biobank. We also conducted a dose-response meta-analysis to integrate the new data with existing prospective evidence. METHODS: 218,237 men from UK Biobank who were free from cancer at baseline were included. Body mass index (BMI), total body fat percentage (using bioimpedance), waist circumference (WC) and waist-to-hip ratio (WHR) were collected at recruitment. Risk of dying from prostate cancer (primary cause) by the different adiposity measurements was estimated using multivariable-adjusted Cox proportional hazards models. Results from this and other prospective cohort studies were combined in a dose-response meta-analysis. RESULTS: In UK Biobank, 661 men died from prostate cancer over a mean follow-up of 11.6 years. In the subsample of participants with magnetic resonance imaging and dual-energy X-ray absorptiometry, BMI, body fat percentage and WC were strongly associated with imaging estimates of total and central adiposity (e.g. visceral fat, trunk fat). The hazard ratios (HR) for prostate cancer death were 1.07 (95% confidence interval = 0.97-1.17) per 5 kg/m2 higher BMI, 1.00 (0.94-1.08) per 5% increase in total body fat percentage, 1.06 (0.99-1.14) per 10 cm increase in WC and 1.07 (1.01-1.14) per 0.05 increase in WHR. Our meta-analyses of prospective studies included 19,633 prostate cancer deaths for BMI, 670 for body fat percentage, 3181 for WC and 1639 for WHR, and the combined HRs for dying from prostate cancer for the increments above were 1.10 (1.07-1.12), 1.03 (0.96-1.11), 1.07 (1.03-1.11), and 1.06 (1.01-1.10), respectively. CONCLUSION: Overall, we found that men with higher total and central adiposity had similarly higher risks of prostate cancer death, which may be biologically driven and/or due to differences in detection. In either case, these findings support the benefit for men of maintaining a healthy body weight.

Risk of cancer in regular and low meat-eaters, fish-eaters, and vegetarians: a prospective analysis of UK Biobank participants.

BACKGROUND: Following a vegetarian diet has become increasingly popular and some evidence suggests that being vegetarian may be associated with a lower risk of cancer overall. However, for specific cancer sites, the evidence is limited. Our aim was to assess the associations of vegetarian and non-vegetarian diets with risks of all cancer, colorectal cancer, postmenopausal breast cancer, and prostate cancer and to explore the role of potential mediators between these associations. METHODS: We conducted a prospective analysis of 472,377 UK Biobank participants who were free from cancer at recruitment. Participants were categorised into regular meat-eaters (n = 247,571), low meat-eaters (n = 205,385), fish-eaters (n = 10,696), and vegetarians (n = 8685) based on dietary questions completed at recruitment. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all cancer incidence and separate cancer sites across diet groups. RESULTS: After an average follow-up of 11.4 years, 54,961 incident cancers were identified, including 5882 colorectal, 7537 postmenopausal breast, and 9501 prostate cancers. Compared with regular meat-eaters, being a low meat-eater, fish-eater, or vegetarian were all associated with a lower risk of all cancer (HR: 0.98, 95% CI: 0.96-1.00; 0.90, 0.84-0.96; 0.86, 0.80-0.93, respectively). Being a low meat-eater was associated with a lower risk of colorectal cancer in comparison to regular meat-eaters (0.91, 0.86-0.96); however, there was heterogeneity in this association by sex (p = 0.007), with an inverse association across diet groups in men, but not in women. Vegetarian postmenopausal women had a lower risk of breast cancer (0.82, 0.68-0.99), which was attenuated and non-significant after adjusting for body mass index (BMI; 0.87, 0.72-1.05); in mediation analyses, BMI was found to possibly mediate the observed association. In men, being a fish-eater or a vegetarian was associated with a lower risk of prostate cancer (0.80, 0.65-0.99 and 0.69, 0.54-0.89, respectively). CONCLUSION: The lower risk of colorectal cancer in low meat-eaters is consistent with previous evidence suggesting an adverse impact of meat intake. The lower risk of postmenopausal breast cancer in vegetarian women may be explained by their lower BMI. It is not clear whether the other differences observed for all cancers and for prostate cancer reflect any causal relationships or are due to other factors such as residual confounding or differences in cancer detection.

Pre-diagnostic C-reactive protein concentrations, CRP genetic variation and mortality among individuals with colorectal cancer in Western European populations.

BACKGROUND: The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear. METHODS: We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression. RESULTS: During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively). CONCLUSIONS: The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention.

Associations Between Macronutrients From Different Dietary Sources and Serum Lipids in 24 639 UK Biobank Study Participants.

[Figure: see text].