Search

Introduction: Observational studies have shown that more educated people are at lower risk of developing type 2 diabetes (T2D). However, robust study designs are needed to investigate the likelihood that such a relationship is causal. This study used genetic instruments for education to estimate the effect of education on T2D using the Mendelian randomisation (MR) approach., Methods: Analyses have been conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study (more than 20 000 individuals), a case-cohort study of T2D nested in the EPIC cohort. Education was measured as Years of Education and Relative Index of Inequality. Prentice-weighted Cox models were performed to estimate the association between education and T2D. One-sample MR analyses investigated whether genetic predisposition towards longer education was associated with risk of T2D and investigated potential mediators of the association., Results: MR estimates indicated a risk reduction of about 15% for each year of longer education on the risk of developing T2D, confirming the protective role estimated by observational models (HR 0.96, 95% CI 0.95 to 0.96). MR analyses on putative mediators showed a significant role of education on body mass index, alcohol consumption, adherence to the Mediterranean diet and smoking habits., Conclusion: The results supported the hypothesis that higher education is a protective factor for the risk of developing T2D. Based on its position in the causal chain, education may be antecedent of other known risk factors for T2D including unhealthy behaviours. These findings reinforce evidence obtained through observational study designs and bridge the gap between correlation and causation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Measuring pre-diagnostic blood metabolites may help identify novel risk factors for prostate cancer. Using data from 4387 matched case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we investigated the associations of 148 individual metabolites and three previously defined metabolite patterns with prostate cancer risk. Metabolites were measured by liquid chromatography-mass spectrometry. Multivariable-adjusted conditional logistic regression was used to estimate the odds ratio per standard deviation increase in log metabolite concentration and metabolite patterns (OR1SD) for prostate cancer overall, and for advanced, high-grade, aggressive. We corrected for multiple testing using the Benjamini-Hochberg method. Overall, there were no associations between specific metabolites or metabolite patterns and overall, aggressive, or high-grade prostate cancer that passed the multiple testing threshold (padj <0.05). Six phosphatidylcholines (PCs) were inversely associated with advanced prostate cancer diagnosed at or within 10 years of blood collection. metabolite patterns 1 (64 PCs and three hydroxysphingomyelins) and 2 (two acylcarnitines, glutamate, ornithine, and taurine) were also inversely associated with advanced prostate cancer; when stratified by follow-up time, these associations were observed for diagnoses at or within 10 years of recruitment (OR 1SD 0.80, 95% CI 0.66-0.96 and 0.76, 0.59-0.97, respectively) but were weaker after longer follow-up (0.95, 0.82-1.10 and 0.85, 0.67-1.06). Pattern 3 (8 lyso PCs) was associated with prostate cancer death (0.82, 0.68-0.98). Our results suggest that the plasma metabolite profile changes in response to the presence of prostate cancer up to a decade before detection of advanced-stage disease., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

We have previously shown that body mass index attenuates a positive association of platelet count (PLT) and inverse of mean platelet volume (MPV) with lung cancer risk in men. It is unclear whether fat mass, lean mass, or liver function tests (LFTs) show similar attenuations. Using bioelectrical impedance measurements (UK Biobank cohort) and multivariable Cox proportional hazards models, we examined the associations of allometric fat-mass index (AFI, fat mass adjusted for height), allometric lean-mass index (ALI, fat-free mass adjusted for height and fat mass), and LFTs with lung cancer risk and their multiplicative and additive interactions with platelet parameters. Based on 1573 lung cancer cases in men and 1473 in women with body composition measurements (1541 in men; 1428 in women with biomarker measurements), AFI in women, ALI in both sexes, alanine aminotransferase (ALT) and total bilirubin in men were inversely associated, while gamma-glutamyl transferase in men and alkaline phosphatase in both sexes were positively associated with lung cancer risk. Only AFI and ALT interacted inversely with PLT and positively with MPV in men. The attenuation of the associations of platelet parameters with lung cancer risk by high-AFI and high-ALT in men suggests that adiposity-related factors hinder lung-cancer-related platelet associations., (© 2024. The Author(s).)

Background: Inflammation influences tumour progression and cancer prognosis, but its role preceding breast cancer (BC) and its prognostic implications remain inconclusive., Methods: We studied pre-diagnostic plasma inflammatory biomarkers in 1538 women with BC from the EPIC study. Cox proportional hazards models assessed their relationship with all-cause and BC-specific mortality, adjusting for tumour characteristics and lifestyle factors., Results: Over a 7-year follow-up after diagnosis, 229 women died, 163 from BC. Elevated IL-6 levels were associated with increased all-cause mortality risk (HR 1-SD 1.25, 95% CI 1.07-1.47). Among postmenopausal, IL-6 was associated with higher all-cause (HR 1-SD 1.41, 95% CI 1.18-1.69) and BC-specific mortality (HR 1-SD 1.31, 95% CI 1.03-1.66), (P Heterogeneity (pre/postmenopausal)  < 0.05 for both), while IL-10 and TNFα were associated with all-cause mortality only (HR 1-SD 1.19, 95% CI 1.02-1.40 and HR 1-SD 1.28, 95% CI 1.06-1.56). Among ER+PR+, IL-10 was associated with all-cause and BC-specific mortality (HR 1-SD 1.35, 95% CI 1.10-1.65 and HR 1-SD 1.42 95% CI 1.08-1.86), while TNF-α was associated with all-cause mortality in HER2- (HR 1-SD 1.31, 95% CI 1.07-1.61). An inflammatory score predicted higher all-cause mortality, especially in postmenopausal women (HR 1-SD 1.30, 95% CI 1.07-1.58)., Conclusions: Higher pre-diagnosis IL-6 levels suggest poorer long-term survival among BC survivors. In postmenopausal survivors, elevated IL-6, IL-10, and TNFα and inflammatory scores seem to predict all-cause mortality., (© 2024. The Author(s).)

Background: Adiposity has been characterized as a modifiable risk factor for prostate cancer. Its association with outcomes after prostate cancer diagnosis, however, must be better understood, and more evidence is needed to facilitate the development of lifestyle guidance for patients with prostate cancer., Methods: We investigated the associations between adiposity indices close to prostate cancer diagnosis (up to 2 years before or up to 5 years after diagnosis) and mortality in 1968 men of the European Prospective Investigation into Cancer and Nutrition cohort. Men were followed up for a median of 9.5 years. Cox proportional hazards models were adjusted for age and year of diagnosis, disease stage and grade, and smoking history and stratified by country., Results: Each 5-unit increment in prediagnosis or postdiagnosis body mass index combined was associated with a 30% higher rate of all-cause mortality and a 49% higher rate of prostate cancer-specific mortality. Similarly, each 5-unit increment in prediagnosis body mass index was associated with a 35% higher rate of all-cause mortality and a 51% higher rate of prostate cancer-specific mortality. The associations were less strong for postdiagnosis body mass index, with a lower number of men in analyses. Less clear positive associations were shown for waist circumference, hip circumference, and waist to hip ratio, but data were limited., Conclusions: Elevated levels of adiposity close to prostate cancer diagnosis could lead to higher risk of mortality; therefore, men are encouraged to maintain a healthy weight. Additional research is needed to confirm whether excessive adiposity after prostate cancer diagnosis could worsen prognosis., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The allometric body shape index (ABSI) and hip index (HI), as well as multi-trait body shape phenotypes, have not yet been compared in their associations with inflammatory markers. The aim of this study was to examine the relationship between novel and traditional anthropometric indexes with inflammation using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts., Methods: Participants from EPIC (n = 17,943, 69.1% women) and UK Biobank (n = 426,223, 53.2% women) with data on anthropometric indexes and C-reactive protein (CRP) were included in this cross-sectional analysis. A subset of women in EPIC also had at least one measurement for interleukins, tumour necrosis factor alpha, interferon gamma, leptin, and adiponectin. Four distinct body shape phenotypes were derived by a principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). PC1 described overall adiposity, PC2 tall with low WHR, PC3 tall and centrally obese, and PC4 high BMI and weight with low WC and HC, suggesting an athletic phenotype. ABSI, HI, waist-to-height ratio and waist-to-hip index (WHI) were also calculated. Linear regression models were carried out separately in EPIC and UK Biobank stratified by sex and adjusted for age, smoking status, education, and physical activity. Results were additionally combined in a random-effects meta-analysis., Results: Traditional anthropometric indexes, particularly BMI, WC, and weight were positively associated with CRP levels, in men and women. Body shape phenotypes also showed distinct associations with CRP. Specifically, PC2 showed inverse associations with CRP in EPIC and UK Biobank in both sexes, similarly to height. PC3 was inversely associated with CRP among women, whereas positive associations were observed among men., Conclusions: Specific indexes of body size and body fat distribution showed differential associations with inflammation in adults. Notably, our results suggest that in women, height may mitigate the impact of a higher WC and HC on inflammation. This suggests that subtypes of adiposity exhibit substantial variation in their inflammatory potential, which may have implications for inflammation-related chronic diseases., (© 2024. The Author(s).)

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, p trend  = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, p trend  = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, p trend  = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women., (© 2024 The World Health Organization. The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Background: Obesity is associated with chronic low-grade inflammation, which is linked to cancer development. Abdominal obesity (a body mass index, ABSI), however, has unusually been associated inversely with cutaneous malignant melanoma (CMM), while general obesity (body mass index, BMI) is associated positively. Leucocytes participate in inflammation and are higher in obesity, but prospective associations of leucocytes with cutaneous malignant melanoma are unclear., Methods: We examined the prospective associations of neutrophil, lymphocyte, and monocyte counts (each individually), as well as the prospective associations of ABSI and BMI, with cutaneous malignant melanoma in UK Biobank. We used multivariable Cox proportional hazards models and explored heterogeneity according to sex, menopausal status, age (≥ 50 years at recruitment), smoking status, ABSI (dichotomised at the median: ≥73.5 women; ≥79.8 men), BMI (normal weight, overweight, obese), and time to diagnosis., Results: During a mean follow-up of 10.2 years, 2174 CMM cases were ascertained in 398,450 participants. There was little evidence for associations with neutrophil or lymphocyte counts. Monocyte count, however, was associated inversely in participants overall (HR = 0.928; 95%CI: 0.888-0.971; per one standard deviation increase; SD = 0.144*10 9 /L women; SD = 0.169*10 9 /L men), specifically in older participants (HR = 0.906; 95%CI: 0.862-0.951), and more clearly in participants with low ABSI (HR = 0.880; 95%CI: 0.824-0.939), or with BMI ≥ 25 kg/m 2 (HR = 0.895; 95%CI: 0.837-0.958 for overweight; HR = 0.923; 95%CI: 0.848-1.005 for obese). ABSI was associated inversely in pre-menopausal women (HR = 0.810; 95%CI: 0.702-0.935; SD = 4.95) and men (HR = 0.925; 95%CI: 0.867-0.986; SD = 4.11). BMI was associated positively in men (HR = 1.148; 95%CI: 1.078-1.222; SD = 4.04 kg/m 2 ). There was little evidence for heterogeneity according to smoking status. The associations with monocyte count and BMI were retained to at least 8 years prior to diagnosis, but the association with ABSI was observed up to 4 years prior to diagnosis and not for longer follow-up time., Conclusions: Monocyte count is associated prospectively inversely with the risk of developing CMM in older individuals, while BMI is associated positively in men, suggesting a mechanistic involvement of factors related to monocytes and subcutaneous adipose tissue in melanoma development. An inverse association with ABSI closer to diagnosis may reflect reverse causality or glucocorticoid resistance., (© 2024. The Author(s).)

Background: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing., Methods: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia., Results: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women., Conclusions: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI., (© 2024. The Author(s).)

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HR Q4vsQ1  = 0.95, 95% CI: 0.73-1.23; P trend  = .97; and HR per doubling of resistin concentration  = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

High cortisol production in Cushing's syndrome leads to fat centralisation. The influence of modest cortisol variations on body shape, however, is less clear. We examined potentially causal associations between morning plasma cortisol and body shape and obesity with inverse-variance weighted random-effects models in a two-sample Mendelian randomisation analysis. We used publicly available summary statistics from the CORtisol NETwork (CORNET) consortium, UK Biobank, and the Genetic Investigation of Anthropometric Traits (GIANT) consortium. Only in women, morning plasma cortisol (proxied by ten genetic polymorphisms) was associated positively with waist size reflected in waist-to-hip index (WHI, 0.035 standard deviation (SD) units change per one SD cortisol increase; 95% confidence interval (0.002-0.067); p = 0.036) and "a body shape index" (ABSI; 0.039 (0.006-0.071); p = 0.021). There was no evidence for associations with hip index (HI) or body mass index (BMI). Among individual polymorphisms, rs7450600 stood out (chromosome 6; Long Intergenic Non-Protein-Coding RNA 473 gene, LINC00473). Morning plasma cortisol proxied by rs7450600 was associated positively with WHI and inversely with HI and BMI in women and men. Our findings support a causal association of higher morning plasma cortisol with larger waist size in women and highlight LINC00473 as a genetic link between morning plasma cortisol and body shape., (© 2024. The Author(s).)

Background: Obesity and diabetes are associated inversely with low-grade prostate cancer risk and affect steroid hormone synthesis but whether they modify each other's impact on prostate cancer risk remains unknown., Methods: We examined the independent associations of diabetes, body mass index (BMI), 'a body shape index' (ABSI), hip index (HI), circulating testosterone, sex hormone binding globulin (SHBG) (per one standard deviation increase) and oestradiol ≥175 pmol/L with total prostate cancer risk using multivariable Cox proportional hazards models for UK Biobank men. We evaluated multiplicative interactions (p MI ) and additive interactions (relative excess risk from interaction (p RERI ), attributable proportion (p AR ), synergy index (p SI )) with obese (BMI ≥30 kg/m 2 ) and diabetes., Results: During a mean follow-up of 10.3 years, 9417 incident prostate cancers were diagnosed in 195,813 men. Diabetes and BMI were associated more strongly inversely with prostate cancer risk when occurring together (p MI  = 0.0003, p RERI  = 0.032, p AP  = 0.020, p SI  = 0.002). ABSI was associated positively in obese men (HR = 1.081; 95% CI = 1.030-1.135) and men with diabetes (HR = 1.114; 95% CI = 1.021-1.216). The inverse associations with obesity and diabetes were attenuated for high-ABSI ≥79.8 (p MI  = 0.022, p RERI  = 0.008, p AP  = 0.005, p SI  <0.0001 obesity; p MI  = 0.017, p RERI  = 0.047, p AP  = 0.025, p SI  = 0.0005 diabetes). HI was associated inversely in men overall (HR = 0.967; 95% CI = 0.947-0.988). Free testosterone (FT) was associated most strongly positively in normal weight men (HR = 1.098; 95% CI = 1.045-1.153) and men with diabetes (HR = 1.189; 95% CI = 1.081-1.308). Oestradiol was associated inversely in obese men (HR = 0.805; 95% CI = 0.682-0.951). The inverse association with obesity was stronger for high-FT ≥243 pmol/L (p RERI  = 0.040, p AP  = 0.031, p SI  = 0.002) and high-oestradiol (p RERI  = 0.030, p AP  = 0.012, p SI  <0.0001). The inverse association with diabetes was attenuated for high-FT (p MI  = 0.008, p RERI  = 0.015, p AP  = 0.009, p SI  = 0.0006). SHBG was associated inversely in men overall (HR = 0.918; 95% CI = 0.895-0.941), more strongly for high-HI ≥49.1 (p MI  = 0.024)., Conclusions: Obesity and diabetes showed synergistic inverse associations with prostate cancer risk, likely involving testosterone reduction for diabetes and oestrogen generation for obesity, which were attenuated for high-ABSI. HI and SHBG showed synergistic inverse associations with prostate cancer risk., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation., Methods: This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established., Results: Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P  = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P  = 0.039) were observed in the study cohort., Conclusions: A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer., Methods: This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI)., Results: In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m 2 ) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m 2 ) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09-0.47)., Conclusions: Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population., (© 2023. The Author(s).)

Background: Platelet count (PLT) is associated positively with lung cancer risk but has a more complex association with body mass index (BMI), positive only in women (mainly never smokers) and inverse in men (mainly ever smokers), raising the question whether platelets interact with obesity in relation to lung cancer risk. Prospective associations of platelet size (an index of platelet maturity and activity) with lung cancer risk are unclear., Methods: We examined the associations of PLT, mean platelet volume (MPV), and platelet distribution width (PDW) (each individually, per one standard deviation increase) with lung cancer risk in UK Biobank men and women using multivariable Cox proportional hazards models adjusted for BMI and covariates. We calculated Relative Excess Risk from Interaction (RERI) with obese (BMI ≥ 30 kg/m 2 ), dichotomising platelet parameters at ≥ median (sex-specific), and multiplicative interactions with BMI (continuous scale). We examined heterogeneity according to smoking status (never, former, current smoker) and antiaggregant/anticoagulant use (no/yes)., Results: During a mean follow-up of 10.4 years, 1620 lung cancers were ascertained in 192,355 men and 1495 lung cancers in 218,761 women. PLT was associated positively with lung cancer risk in men (hazard ratio HR = 1.14; 95% confidence interval (CI): 1.09-1.20) and women (HR = 1.09; 95%CI: 1.03-1.15) but interacted inversely with BMI only in men (RERI = - 0.53; 95%CI: - 0.80 to - 0.26 for high-PLT-obese; HR = 0.92; 95%CI = 0.88-0.96 for PLT*BMI). Only in men, MPV was associated inversely with lung cancer risk (HR = 0.95; 95%CI: 0.90-0.99) and interacted positively with BMI (RERI = 0.27; 95%CI = 0.09-0.45 for high-MPV-obese; HR = 1.08; 95%CI = 1.04-1.13 for MPV*BMI), while PDW was associated positively (HR = 1.05; 95%CI: 1.00-1.10), with no evidence for interactions. The associations with PLT were consistent by smoking status, but MPV was associated inversely only in current smokers and PDW positively only in never/former smokers. The interactions with BMI were retained for at least eight years of follow-up and were consistent by smoking status but were attenuated in antiaggregant/anticoagulant users., Conclusions: In men, PLT was associated positively and MPV inversely with lung cancer risk and these associations appeared hindered by obesity. In women, only PLT was associated positively, with little evidence for interaction with obesity., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach., Methods: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry., Results: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37)., Conclusions: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Obesity is associated with type 2 diabetes mellitus and chronic low-grade inflammation. Although chronic inflammatory conditions and diabetes are associated with anaemia, less is known about associations of obesity and body shape, independent of each other, with erythrocyte and reticulocyte parameters., Methods: We investigated the associations of body mass index (BMI) and the allometric body shape index (ABSI) and hip index (HI), which are uncorrelated with BMI, with erythrocyte and reticulocyte parameters (all continuous, on a standard deviation (SD) scale) in UK Biobank participants without known metabolic, endocrine, or major inflammatory conditions (glycated haemoglobin HbA1c < 48 mmol/mol, C-reactive protein CRP < 10 mg/L). We examined erythrocyte count, total reticulocyte count and percent, immature reticulocyte count and fraction (IRF), haemoglobin, haematocrit, mean corpuscular haemoglobin mass (MCH) and concentration (MCHC), mean corpuscular and reticulocyte volumes (MCV, MRV), and red cell distribution width (RDW) in multivariable linear regression models. We additionally defined body shape phenotypes with dichotomised ABSI (≥ 73 women; ≥ 80 men) and HI (≥ 64 women; ≥ 49 men), including "pear" (small-ABSI-large-HI) and "apple" (large-ABSI-small-HI), and examined these in groups according to BMI (18.5-25 normal weight; 25-30 overweight; 30-45 kg/m 2 obese)., Results: In 105,853 women and 100,854 men, BMI and ABSI were associated positively with haemoglobin, haematocrit, and erythrocyte count, and more strongly with total reticulocyte count and percent, immature reticulocyte count and IRF. HI was associated inversely with all, but least with IRF. Associations were comparable in women and men. In groups according to obesity and body shape, erythrocyte count was ~ 0.6 SD higher for obese-"apple" compared to normal-weight-"pear" phenotype (SD = 0.31*10 12 /L women, SD = 0.34*10 12 /L men), total reticulocyte count was ~ 1.1 SD higher (SD = 21.1*10 9 /L women, SD = 23.6*10 9 /L men), immature reticulocyte count was ~ 1.2 SD higher (SD = 7.9*10 9 /L women, SD = 8.8*10 9 /L men), total reticulocyte percent was ~ 1.0 SD higher (SD = 0.48% women and men), and IFR was over 0.7 SD higher (SD = 5.7% women and men). BMI but not ABSI or HI was associated more weakly inversely with MCV, MRV, and MCH, but positively with MCHC in men and RDW in women., Conclusions: In obesity uncomplicated with diabetes, larger BMI and ABSI are associated with increased erythropoiesis and reticulocyte immaturity., (© 2023. The Author(s).)

Background & Aims: Cell-derived small extracellular vesicles (sEVs) participate in cell-cell communication via the transfer of molecular cargo including selectively enriched microRNAs (miRNAs). Utilizing advances in sEV isolation and characterization, this study investigates the impact of liver injury and dysfunction on the circulating EV-miRNA profile., Methods: High-throughput screening of 799 sEV-miRNAs isolated from plasma was performed in patients across a spectrum of liver disorders including compensated and decompensated chronic liver disease, acute-on-chronic liver failure (ACLF), and acute liver failure, in addition to healthy controls and those with severe sepsis. miRNA levels were compared with clinical and biochemical parameters, composite scores of liver disease, and patient outcomes., Results: miRNA screening revealed the degree of hepatic dysfunction to be the main determinant of changes in circulating sEV-miRNA profile, with liver-specific miRNA-122 being among the most highly dysregulated in severe injury. Principal components analyses of the 215 differentially expressed miRNAs showed differing profiles, particularly among those with acute liver injury and ACLF. A distinct profile of dysregulated miRNA, but not circulating cytokines, was shown to characterize ACLF, with four consensus miRNAs identified-miR-320e, miR-374-5p, miR-202-3p, and miR-1910-5p. High miR-320e was associated with poorer 90-day survival (p = 0.014) and regulated the functional gene targets IK, RPS5, MANBAL, and PEBP1., Conclusions: This first comprehensive analysis to the best of our knowledge of patients with varying degrees and stages of liver failure demonstrates miRNA profiles specifically within the sEV compartment to be significantly altered in progressive liver disease and highlights the diagnostic and prognostic potential of sEV-miRNA in ACLF while also establishing downstream gene targets., (© 2023 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5-15%) increase in overall mortality and 7% (0-15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11-37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival., (© 2023. The Author(s).)

Background: Inflammatory, insulin and oestrogenic pathways have been linked to breast cancer (BC). We aimed to examine the relationship between pre-diagnostic dietary patterns related to these mechanisms and BC survival., Methods: The diabetes risk reduction diet (DRRD), inflammatory score of diet (ISD) and oestrogen-related dietary pattern (ERDP) were calculated using dietary data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to assess associations between dietary patterns and overall mortality and competing risk models for associations with BC-specific mortality., Results: We included 13,270 BC cases with a mean follow-up after diagnosis of 8.6 years, representing 2340 total deaths, including 1475 BC deaths. Higher adherence to the DRRD score was associated with lower overall mortality (HR 1-SD 0.92; 95%CI 0.87-0.96). Greater adherence to pro-inflammatory diets was borderline associated with 6% higher mortality HR 1-SD 1.06; 95%CI 1.00-1.12. No significant association with the oestrogen-related dietary pattern was observed. None of the dietary patterns were associated with BC-specific mortality., Conclusions: Greater adherence to an anti-diabetic and anti-inflammatory diet prior to diagnosis is associated with lower overall mortality among BC survivors. Long-term adherence to these dietary patterns could be a means to improve the prognosis of BC survivors., (© 2023. The Author(s).)