Alcohol intake and endogenous sex hormones in women: Meta-analysis of cohort studies and Mendelian randomization.

BACKGROUND: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. METHODS: Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). RESULTS: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). CONCLUSIONS: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition.

BACKGROUND: Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk. METHODS: We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics. RESULTS: Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade. CONCLUSIONS: Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.

Dietary amino acids and risk of stroke subtypes: a prospective analysis of 356,000 participants in seven European countries.

PURPOSE: Previously reported associations of protein-rich foods with stroke subtypes have prompted interest in the assessment of individual amino acids. We examined the associations of dietary amino acids with risks of ischaemic and haemorrhagic stroke in the EPIC study. METHODS: We analysed data from 356,142 participants from seven European countries. Dietary intakes of 19 individual amino acids were assessed using validated country-specific dietary questionnaires, calibrated using additional 24-h dietary recalls. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of ischaemic and haemorrhagic stroke in relation to the intake of each amino acid. The role of blood pressure as a potential mechanism was assessed in 267,642 (75%) participants. RESULTS: After a median follow-up of 12.9 years, 4295 participants had an ischaemic stroke and 1375 participants had a haemorrhagic stroke. After correction for multiple testing, a higher intake of proline (as a percent of total protein) was associated with a 12% lower risk of ischaemic stroke (HR per 1 SD higher intake 0.88; 95% CI 0.82, 0.94). The association persisted after mutual adjustment for all other amino acids, systolic and diastolic blood pressure. The inverse associations of isoleucine, leucine, valine, phenylalanine, threonine, tryptophan, glutamic acid, serine and tyrosine with ischaemic stroke were each attenuated with adjustment for proline intake. For haemorrhagic stroke, no statistically significant associations were observed in the continuous analyses after correcting for multiple testing. CONCLUSION: Higher proline intake may be associated with a lower risk of ischaemic stroke, independent of other dietary amino acids and blood pressure.

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.

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.

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.

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.

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.

Dairy consumption and risks of total and site-specific cancers in Chinese adults: an 11-year prospective study of 0.5 million people.

BACKGROUND: Previous studies of primarily Western populations have reported contrasting associations of dairy consumption with certain cancers, including a positive association with prostate cancer and inverse associations with colorectal and premenopausal breast cancers. However, there are limited data from China where cancer rates and levels of dairy consumption differ importantly from those in Western populations. METHODS: The prospective China Kadoorie Biobank study recruited ~0.5 million adults from ten diverse (five urban, five rural) areas across China during 2004-2008. Consumption frequency of major food groups, including dairy products, was collected at baseline and subsequent resurveys, using a validated interviewer-administered laptop-based food frequency questionnaire. To quantify the linear association of dairy intake and cancer risk and to account for regression dilution bias, the mean usual consumption amount for each baseline group was estimated via combining the consumption level at both baseline and the second resurvey. During a mean follow-up of 10.8 (SD 2.0) years, 29,277 incident cancer cases were recorded among the 510,146 participants who were free of cancer at baseline. Cox regression analyses for incident cancers associated with usual dairy intake were stratified by age-at-risk, sex and region and adjusted for cancer family history, education, income, alcohol intake, smoking, physical activity, soy and fresh fruit intake, and body mass index. RESULTS: Overall, 20.4% of participants reported consuming dairy products (mainly milk) regularly (i.e. ≥1 day/week), with the estimated mean consumption of 80.8 g/day among regular consumers and of 37.9 g/day among all participants. There were significant positive associations of dairy consumption with risks of total and certain site-specific cancers, with adjusted HRs per 50 g/day usual consumption being 1.07 (95% CI 1.04-1.10), 1.12 (1.02-1.22), 1.19 (1.01-1.41) and 1.17 (1.07-1.29) for total cancer, liver cancer (n = 3191), female breast cancer (n = 2582) and lymphoma (n=915), respectively. However, the association with lymphoma was not statistically significant after correcting for multiple testing. No significant associations were observed for colorectal cancer (n = 3350, 1.08 [1.00-1.17]) or other site-specific cancers. CONCLUSION: Among Chinese adults who had relatively lower dairy consumption than Western populations, higher dairy intake was associated with higher risks of liver cancer, female breast cancer and, possibly, lymphoma.

Higher Meat Intake Is Associated with Higher Inflammatory Markers, Mostly Due to Adiposity: Results from UK Biobank.

BACKGROUND: High meat consumption might play a role in promoting low-grade systemic inflammation, but evidence is limited. OBJECTIVES: We examined cross-sectional associations of habitual meat consumption with serum C-reactive protein (CRP) and total white blood cell count (WBCC) in British adults. METHODS: We included 403,886 men and women (aged 38-73 y) participating in the UK Biobank who provided information on meat intake (via touchscreen questionnaire) and a nonfasting blood sample at recruitment (2006-2010). For a subset of participants (∼5%), an additional blood sample was collected (median 4.4 y later). We used multivariable linear regression models to estimate associations of meat intake (total meat, unprocessed red meat, processed meat, and poultry) with logCRP and logWBCC. RESULTS: The difference in the serum CRP (mg/L) for each 50-g/d higher intake for total meat was 11.6% (95% CI: 11.1, 12.0%), for processed meat was 38.3% (95% CI: 36.0, 40.7%), for unprocessed red meat was 14.4% (95% CI: 13.6, 15.1%), and for poultry was 12.8% (95% CI: 12.0, 13.5%). The difference in the WBCC (×10-9L) for each 50 g/d higher intake of total meat was 1.5% (95% CI: 1.4, 1.6%), for processed meat was 6.5% (95% CI: 6.1, 6.9%), for unprocessed red meat was 1.6% (95% CI: 1.4, 1.7%), and for poultry was 1.6% (95% CI: 1.4, 1.7%). All associations were attenuated after adjustment for adiposity; by 67% with BMI (in kg/m2) and by 58% with waist circumference for total meat and CRP, and by 53% and 47%, respectively, for WBCC, although associations remained statistically significant. Findings of sensitivity analyses in 15,420 participants were similar prospectively, except there were no associations between unprocessed red meat and WBCC. CONCLUSIONS: Higher meat consumption, particularly of processed meat, was positively associated with inflammatory markers in these British adults; however, the magnitudes of associations are small and predominantly due to higher adiposity.

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

[Figure: see text].

Circulating insulin-like growth factor-I and risk of 25 common conditions: outcome-wide analyses in the UK Biobank study.

While there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort. Study participants were 318,749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006-2010), and re-measured in 12,334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias. After correction for multiple testing (P < 0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration = 1.12, 95% CI 1.08-1.16), and inversely associated with varicose veins (0.90, 0.85-0.95), cataracts (0.97, 0.95-0.99), diabetes (0.92, 0.90-0.95), and iron deficiency anaemia (0.90, 0.86-0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality. Higher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal.

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction.

BACKGROUND: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. OBJECTIVE: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. METHODS: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes. RESULTS: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10-10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10-8, highest vs lowest quintile of the weighted multifactorial score). CONCLUSION: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

Prospective analyses of testosterone and sex hormone-binding globulin with the risk of 19 types of cancer in men and postmenopausal women in UK Biobank.

We investigated the associations of estimated free and total circulating testosterone and sex hormone-binding globulin (SHBG) with cancer risk in men and postmenopausal women, using a pan-cancer approach, including 19 cancers in UK Biobank. Risk was estimated using multivariable-adjusted Cox regression in up to 182 608 men and 122 112 postmenopausal women who were cancer-free at baseline. Participants diagnosed with cancer within 2 years of baseline were excluded. Hazard ratios (HRs) and confidence intervals (CIs) were corrected for regression dilution bias using repeat measurements. We accounted for multiple testing using the false discovery rate. In men, higher free testosterone was associated with higher risks of melanoma and prostate cancer (HR per 50 pmol/L increase = 1.35, 95% CI 1.14-1.61 and 1.10, 1.04-1.18, respectively). Higher total testosterone was associated with an elevated risk of liver cancer (HR per 5 nmol/L = 2.45, 1.56-3.84), and higher SHBG was associated with a higher risk of liver cancer (HR per 10 nmol/L = 1.56, 1.31-1.87) and a lower risk of prostate cancer (0.93, 0.91-0.96); the associations with liver cancer were partially attenuated after excluding men diagnosed within 4.7 years from baseline. In postmenopausal women, free and total testosterone and SHBG were associated with risks of endometrial (HR per 10 pmol/L = 1.59, 1.32-1.90; HR per 0.5 nmol/L = 1.34, 1.18-1.52 and HR per 25 nmol/L = 0.78, 0.67-0.91, respectively) and breast cancer (1.32, 1.22-1.43; 1.24, 1.17-1.31 and 0.88, 0.83-0.94, respectively). We report a novel association of free testosterone with malignant melanoma in men, and confirm known associations between testosterone and risks for prostate, breast and endometrial cancers. The association with liver cancer in men may be attributable to reverse causation.

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.

Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two-sample Mendelian randomisation (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis- and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment = 1.34, 1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.

Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.

Endogenous hormones and risk of invasive breast cancer in pre- and post-menopausal women: findings from the UK Biobank.

BACKGROUND: Some endogenous hormones have been associated with breast cancer risk, but the nature of these relationships is not fully understood. METHODS: UK Biobank was used. Hormone concentrations were measured in serum collected in 2006-2010, and in a repeat subsample (N ~ 5000) in 2012-13. Incident cancers were identified through data linkage. Cox regression models were used, and hazard ratios (HRs) corrected for regression dilution bias. RESULTS: Among 30,565 pre-menopausal and 133,294 post-menopausal women, 527 and 2,997, respectively, were diagnosed with invasive breast cancer during a median follow-up of 7.1 years. Cancer risk was positively associated with testosterone in post-menopausal women (HR per 0.5 nmol/L increment: 1.18; 95% CI: 1.14, 1.23) but not in pre-menopausal women (pheterogeneity = 0.03), and with IGF-1 (insulin-like growth factor-1) (HR per 5 nmol/L increment: 1.18; 1.02, 1.35 (pre-menopausal) and 1.07; 1.01, 1.12 (post-menopausal); pheterogeneity = 0.2), and inversely associated with SHBG (sex hormone-binding globulin) (HR per 30 nmol/L increment: 0.96; 0.79, 1.15 (pre-menopausal) and 0.89; 0.84, 0.94 (post-menopausal); pheterogeneity = 0.4). Oestradiol, assessed only in pre-menopausal women, was not associated with risk, but there were study limitations for this hormone. CONCLUSIONS: This study confirms associations of testosterone, IGF-1 and SHBG with breast cancer risk, with heterogeneity by menopausal status for testosterone.

Meat consumption and risk of 25 common conditions: outcome-wide analyses in 475,000 men and women in the UK Biobank study.

BACKGROUND: There is limited prospective evidence on the association between meat consumption and many common, non-cancerous health outcomes. We examined associations of meat intake with risk of 25 common conditions (other than cancer). METHODS: We used data from 474,985 middle-aged adults recruited into the UK Biobank study between 2006 and 2010 and followed up until 2017 (mean follow-up 8.0 years) with available information on meat intake at baseline (collected via touchscreen questionnaire), and linked hospital admissions and mortality data. For a large sub-sample (~ 69,000), dietary intakes were re-measured three or more times using an online, 24-h recall questionnaire. RESULTS: On average, participants who reported consuming meat regularly (three or more times per week) had more adverse health behaviours and characteristics than participants who consumed meat less regularly, and most of the positive associations observed for meat consumption and health risks were substantially attenuated after adjustment for body mass index (BMI). In multi-variable adjusted (including BMI) Cox regression models corrected for multiple testing, higher consumption of unprocessed red and processed meat combined was associated with higher risks of ischaemic heart disease (hazard ratio (HRs) per 70 g/day higher intake 1.15, 95% confidence intervals (CIs) 1.07-1.23), pneumonia (1.31, 1.18-1.44), diverticular disease (1.19, 1.11-1.28), colon polyps (1.10, 1.06-1.15), and diabetes (1.30, 1.20-1.42); results were similar for unprocessed red meat and processed meat intakes separately. Higher consumption of unprocessed red meat alone was associated with a lower risk of iron deficiency anaemia (IDA: HR per 50 g/day higher intake 0.80, 95% CIs 0.72-0.90). Higher poultry meat intake was associated with higher risks of gastro-oesophageal reflux disease (HR per 30 g/day higher intake 1.17, 95% CIs 1.09-1.26), gastritis and duodenitis (1.12, 1.05-1.18), diverticular disease (1.10, 1.04-1.17), gallbladder disease (1.11, 1.04-1.19), and diabetes (1.14, 1.07-1.21), and a lower IDA risk (0.83, 0.76-0.90). CONCLUSIONS: Higher unprocessed red meat, processed meat, and poultry meat consumption was associated with higher risks of several common conditions; higher BMI accounted for a substantial proportion of these increased risks suggesting that residual confounding or mediation by adiposity might account for some of these remaining associations. Higher unprocessed red meat and poultry meat consumption was associated with lower IDA risk.