Publications by authors named "Alicia K Heath"

38 Publications

Association between circulating 25-hydroxyvitamin D concentrations and hip replacement for osteoarthritis: a prospective cohort study.

BMC Musculoskelet Disord 2021 Oct 19;22(1):887. Epub 2021 Oct 19.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne, VIC, 3004, Australia.

Background: To examine the association between circulating 25(OH)D concentrations and incidence of total hip replacement for osteoarthritis in a prospective cohort study.

Methods: This study examined a random sample of 2651 participants in the Melbourne Collaborative Cohort Study who had 25(OH)D concentrations measured from dried blood spots collected in 1990-1994. Participants who underwent total hip replacement for osteoarthritis between January 2001 and December 2018 were identified by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of total hip replacement for osteoarthritis in relation to 25(OH)D concentrations, adjusted for confounders.

Results: Eighty-six men and eighty-seven women had a total hip replacement for osteoarthritis. Compared with men in the lowest (1st) quartile of 25(OH)D concentration, the HR for total hip replacement was 2.32 (95% CI 1.05, 5.13) for those in the 2nd quartile, 2.77 (95% CI 1.28, 6.00) for those in the 3rd quartile, and 1.73 (95% CI 0.75, 4.02) for those in the highest quartile of 25(OH)D concentrations (p for trend 0.02). There was little evidence of an association in women.

Conclusions: Higher circulating 25(OH)D concentrations were associated with an increased risk of total hip replacement for osteoarthritis in men but not in women. Although the underlying mechanism warrants further investigation, our findings highlight the need to determine the optimal levels of circulating 25(OH)D to reduce the risk of hip osteoarthritis.
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http://dx.doi.org/10.1186/s12891-021-04779-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524987PMC
October 2021

Dietary Advanced Glycation End-Products and Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

Nutrients 2021 Sep 8;13(9). Epub 2021 Sep 8.

Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain.

Dietary advanced glycation end-products (dAGEs) have been hypothesized to be associated with a higher risk of colorectal cancer (CRC) by promoting inflammation, metabolic dysfunction, and oxidative stress in the colonic epithelium. However, evidence from prospective cohort studies is scarce and inconclusive. We evaluated CRC risk associated with the intake of dAGEs in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intakes of three major dAGEs: N-carboxy-methyllysine (CML), N-carboxyethyllysine (CEL), and N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated in 450,111 participants (median follow-up = 13 years, with 6162 CRC cases) by matching to a detailed published European food composition database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of dAGEs with CRC were computed using multivariable-adjusted Cox regression models. Inverse CRC risk associations were observed for CML (HR comparing extreme quintiles: HR. = 0.92, 95% CI = 0.85-1.00) and MG-H1 (HR. = 0.92, 95% CI = 0.85-1.00), but not for CEL (HR. = 0.97, 95% CI = 0.89-1.05). The associations did not differ by sex or anatomical location of the tumor. Contrary to the initial hypothesis, our findings suggest an inverse association between dAGEs and CRC risk. More research is required to verify these findings and better differentiate the role of dAGEs from that of endogenously produced AGEs and their precursor compounds in CRC development.
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http://dx.doi.org/10.3390/nu13093132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470201PMC
September 2021

Consumption of ultra-processed foods associated with weight gain and obesity in adults: A multi-national cohort study.

Clin Nutr 2021 09 21;40(9):5079-5088. Epub 2021 Aug 21.

Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Background: There is a worldwide shift towards increased consumption of ultra-processed foods (UPF) with concurrent rising prevalence of obesity. We examined the relationship between the consumption of UPF and weight gain and risk of obesity.

Methods: This prospective cohort included 348 748 men and women aged 25-70 years. Participants were recruited between 1992 and 2000 from 9 European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Two body weight measures were available, at baseline and after a median follow-up time of 5 years. Foods and drinks were assessed at baseline by dietary questionnaires and classified according to their degree of processing using NOVA classification. Multilevel mixed linear regression was used to estimate the association between UPF consumption and body weight change (kg/5 years). To estimate the relative risk of becoming overweight or obese after 5 years we used Poisson regression stratified according to baseline body mass index (BMI).

Results: After multivariable adjustment, higher UPF consumption (per 1 SD increment) was positively associated with weight gain (0·12 kg/5 years, 95% CI 0·09 to 0·15). Comparing highest vs. lowest quintile of UPF consumption was associated with a 15% greater risk (95% CI 1·11, 1·19) of becoming overweight or obese in normal weight participants, and with a 16% greater risk (95% CI 1·09, 1·23) of becoming obese in participants who were overweight at baseline.

Conclusions: These results are supportive of public health campaigns to substitute UPF for less processed alternatives for obesity prevention and weight management.
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http://dx.doi.org/10.1016/j.clnu.2021.08.009DOI Listing
September 2021

Association of Cycling With All-Cause and Cardiovascular Disease Mortality Among Persons With Diabetes: The European Prospective Investigation Into Cancer and Nutrition (EPIC) Study.

JAMA Intern Med 2021 Sep;181(9):1196-1205

University of Southern Denmark, Odense, Denmark.

Importance: Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes.

Objective: To investigate the association between time spent cycling and all-cause and CVD mortality among persons with diabetes, as well as to evaluate the association between change in time spent cycling and risk of all-cause and CVD mortality.

Design, Setting, And Participants: This prospective cohort study included 7459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition study. Questionnaires regarding medical history, sociodemographic, and lifestyle information were administered in 10 Western European countries from 1992 through 2000 (baseline examination) and at a second examination 5 years after baseline. A total of 5423 participants with diabetes completed both examinations. The final updated primary analysis was conducted on November 13, 2020.

Exposures: The primary exposure was self-reported time spent cycling per week at the baseline examination. The secondary exposure was change in cycling status from baseline to the second examination.

Main Outcomes And Measures: The primary and secondary outcomes were all-cause and CVD mortality, respectively, adjusted for other physical activity modalities, diabetes duration, and sociodemographic and lifestyle factors.

Results: Of the 7459 adults with diabetes included in the analysis, the mean (SD) age was 55.9 (7.7) years, and 3924 (52.6%) were female. During 110 944 person-years of follow-up, 1673 deaths from all causes were registered. Compared with the reference group of people who reported no cycling at baseline (0 min/wk), the multivariable-adjusted hazard ratios for all-cause mortality were 0.78 (95% CI, 0.61-0.99), 0.76 (95% CI, 0.65-0.88), 0.68 (95% CI, 0.57-0.82), and 0.76 (95% CI, 0.63-0.91) for cycling 1 to 59, 60 to 149, 150 to 299, and 300 or more min/wk, respectively. In an analysis of change in time spent cycling with 57 802 person-years of follow-up, a total of 975 deaths from all causes were recorded. Compared with people who reported no cycling at both examinations, the multivariable-adjusted hazard ratios for all-cause mortality were 0.90 (95% CI, 0.71-1.14) in those who cycled and then stopped, 0.65 (95% CI, 0.46-0.92) in initial noncyclists who started cycling, and 0.65 (95% CI, 0.53-0.80) for people who reported cycling at both examinations. Similar results were observed for CVD mortality.

Conclusion And Relevance: In this cohort study, cycling was associated with lower all-cause and CVD mortality risk among people with diabetes independent of practicing other types of physical activity. Participants who took up cycling between the baseline and second examination had a considerably lower risk of both all-cause and CVD mortality compared with consistent noncyclists.
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http://dx.doi.org/10.1001/jamainternmed.2021.3836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290339PMC
September 2021

Plasma concentrations of persistent organic pollutants and pancreatic cancer risk.

Int J Epidemiol 2021 Jul 14. Epub 2021 Jul 14.

Cancer Registry and Histopathology Department, "Civic-M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.

Background: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts.

Methods: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline.

Results: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk.

Conclusions: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.
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http://dx.doi.org/10.1093/ije/dyab115DOI Listing
July 2021

Prospective analysis of circulating metabolites and endometrial cancer risk.

Gynecol Oncol 2021 Aug 5;162(2):475-481. Epub 2021 Jun 5.

Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.

Background: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed.

Results: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR: 0.89, 95% CI: 0.80-0.99; OR: 0.89, 95% CI: 0.79-1.00 and OR: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results.

Conclusion: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.
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http://dx.doi.org/10.1016/j.ygyno.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336647PMC
August 2021

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Nutrients 2021 May 28;13(6). Epub 2021 May 28.

Office of the Director, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France.

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.
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http://dx.doi.org/10.3390/nu13061843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228096PMC
May 2021

Metabolic signatures of greater body size and their associations with risk of colorectal and endometrial cancers in the European Prospective Investigation into Cancer and Nutrition.

BMC Med 2021 04 30;19(1):101. Epub 2021 Apr 30.

International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: The mechanisms underlying the obesity-cancer relationship are incompletely understood. This study aimed to characterise metabolic signatures of greater body size and to investigate their association with two obesity-related malignancies, endometrial and colorectal cancers, and with weight loss within the context of an intervention study.

Methods: Targeted mass spectrometry metabolomics data from 4326 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 17 individuals from a single-arm pilot weight loss intervention (Intercept) were used in this analysis. Metabolic signatures of body size were first determined in discovery (N = 3029) and replication (N = 1297) sets among EPIC participants by testing the associations between 129 metabolites and body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) using linear regression models followed by partial least squares analyses. Conditional logistic regression models assessed the associations between the metabolic signatures with endometrial (N = 635 cases and 648 controls) and colorectal (N = 423 cases and 423 controls) cancer risk using nested case-control studies in EPIC. Pearson correlation between changes in the metabolic signatures and weight loss was tested among Intercept participants.

Results: After adjustment for multiple comparisons, greater BMI, WC, and WHR were associated with higher levels of valine, isoleucine, glutamate, PC aa C38:3, and PC aa C38:4 and with lower levels of asparagine, glutamine, glycine, serine, lysoPC C17:0, lysoPC C18:1, lysoPC C18:2, PC aa C42:0, PC ae C34:3, PC ae C40:5, and PC ae C42:5. The metabolic signature of BMI (OR 1.50, 95% CI 1.30-1.74), WC (OR 1.46, 95% CI 1.27-1.69), and WHR (OR 1.54, 95% CI 1.33-1.79) were each associated with endometrial cancer risk. Risk of colorectal cancer was positively associated with the metabolic signature of WHR (OR: 1.26, 95% CI 1.07-1.49). In the Intercept study, a positive correlation was observed between weight loss and changes in the metabolic signatures of BMI (r = 0.5, 95% CI 0.06-0.94, p = 0.03), WC (r = 0.5, 95% CI 0.05-0.94, p = 0.03), and WHR (r = 0.6, 95% CI 0.32-0.87, p = 0.01).

Conclusions: Obesity is associated with a distinct metabolic signature comprising changes in levels of specific amino acids and lipids which is positively associated with both colorectal and endometrial cancer and is potentially reversible following weight loss.
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http://dx.doi.org/10.1186/s12916-021-01970-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086283PMC
April 2021

Dietary intake and plasma phospholipid concentrations of saturated, monounsaturated and trans fatty acids and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

Int J Cancer 2021 Apr 28. Epub 2021 Apr 28.

Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden.

Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial-processed trans (iTFA), and ruminant-sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow-up = 15 years). In a nested case-control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable-adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HR  = 0.80; 95%CI:0.69-0.92), myristic acid (HR  = 0.83, 95%CI:0.74-0.93) and palmitic acid (HR  = 0.81, 95%CI:0.70-0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, OR  = 0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (OR  = 1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR  = 0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR  = 1.04, 95%CI:0.95-1.15, P  = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR  = 1.07, 95%CI:1.02-1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.
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http://dx.doi.org/10.1002/ijc.33615DOI Listing
April 2021

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

Clin Gastroenterol Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.cgh.2021.04.028DOI Listing
April 2021

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

Cancer Epidemiol Biomarkers Prev 2021 06 13;30(6):1270-1274. Epub 2021 Apr 13.

International Agency for Research on Cancer (IARC-WHO), Lyon, France.

Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks.

Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively).

Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity.

Impact: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611361PMC
June 2021

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Am J Clin Nutr 2021 07;114(1):338-347

Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.

Background: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health.

Objectives: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics.

Medthods: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP.

Results: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers.

Conclusions: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.
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http://dx.doi.org/10.1093/ajcn/nqab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246608PMC
July 2021

Dietary intake of trans fatty acids and breast cancer risk in 9 European countries.

BMC Med 2021 03 30;19(1):81. Epub 2021 Mar 30.

Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden.

Background: Trans fatty acids (TFAs) have been hypothesised to influence breast cancer risk. However, relatively few prospective studies have examined this relationship, and well-powered analyses according to hormone receptor-defined molecular subtypes, menopausal status, and body size have rarely been conducted.

Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between dietary intakes of TFAs (industrial trans fatty acids [ITFAs] and ruminant trans fatty acids [RTFAs]) and breast cancer risk among 318,607 women. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for other breast cancer risk factors.

Results: After a median follow-up of 8.1 years, 13,241 breast cancer cases occurred. In the multivariable-adjusted model, higher total ITFA intake was associated with elevated breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). A similar positive association was found between intake of elaidic acid, the predominant ITFA, and breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). Intake of total RTFAs was also associated with higher breast cancer risk (HR for highest vs lowest quintile, 1.09, 95% CI 1.01-1.17; P trend = 0.015). For individual RTFAs, we found positive associations with breast cancer risk for dietary intakes of two strongly correlated fatty acids (Spearman correlation r = 0.77), conjugated linoleic acid (HR for highest vs lowest quintile, 1.11, 95% CI 1.03-1.20; P trend = 0.001) and palmitelaidic acid (HR for highest vs lowest quintile, 1.08, 95% CI 1.01-1.16; P trend = 0.028). Similar associations were found for total ITFAs and RTFAs with breast cancer risk according to menopausal status, body mass index, and breast cancer subtypes.

Conclusions: These results support the hypothesis that higher dietary intakes of ITFAs, in particular elaidic acid, are associated with elevated breast cancer risk. Due to the high correlation between conjugated linoleic acid and palmitelaidic acid, we were unable to disentangle the positive associations found for these fatty acids with breast cancer risk. Further mechanistic studies are needed to identify biological pathways that may underlie these associations.
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http://dx.doi.org/10.1186/s12916-021-01952-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008592PMC
March 2021

Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.

Carcinogenesis 2021 05;42(5):705-713

Office of the Director, International Agency for Research on Cancer (IARC), Lyon, France.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort. Plasma concentrations of three protein-bound AGEs-Nε-(carboxy-methyl)lysine (CML), Nε-(carboxy-ethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)-were measured by ultra-performance liquid chromatography-tandem mass spectrometry in baseline samples collected from 1378 incident primary colorectal cancer cases and 1378 matched controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression for colorectal cancer risk associated with CML, CEL, MG-H1, total AGEs, and [CEL+MG-H1: CML] and [CEL:MG-H1] ratios. Inverse colorectal cancer risk associations were observed for CML (OR comparing highest to lowest quintile, ORQ5 versus Q1 = 0.40, 95% CI: 0.27-0.59), MG-H1 (ORQ5 versus Q1 = 0.73, 95% CI: 0.53-1.00) and total AGEs (OR Q5 versus Q1 = 0.52, 95% CI: 0.37-0.73), whereas no association was observed for CEL. A higher [CEL+MG-H1: CML] ratio was associated with colorectal cancer risk (ORQ5 versus Q1 = 1.91, 95% CI: 1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical sub-site. Although individual AGEs concentrations appear to be inversely associated with colorectal cancer risk, a higher ratio of methylglyoxal-derived AGEs versus those derived from glyoxal (calculated by [CEL+MG-H1: CML] ratio) showed a strong positive risk association. Further insight on the metabolism of AGEs and their dicarbonyls precursors, and their roles in colorectal cancer development is needed.
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http://dx.doi.org/10.1093/carcin/bgab026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162627PMC
May 2021

Long-term weight change and risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Int J Epidemiol 2021 Mar 23. Epub 2021 Mar 23.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, UK.

Background: The role of obesity and weight change in breast-cancer development is complex and incompletely understood. We investigated long-term weight change and breast-cancer risk by body mass index (BMI) at age 20 years, menopausal status, hormone replacement therapy (HRT) and hormone-receptor status.

Methods: Using data on weight collected at three different time points from women who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we investigated the association between weight change from age 20 years until middle adulthood and risk of breast cancer.

Results: In total, 150 257 women with a median age of 51 years at cohort entry were followed for an average of 14 years (standard deviation = 3.9) during which 6532 breast-cancer cases occurred. Compared with women with stable weight (±2.5 kg), long-term weight gain >10 kg was positively associated with postmenopausal breast-cancer risk in women who were lean at age 20 [hazard ratio (HR) = 1.42; 95% confidence interval 1.22-1.65] in ever HRT users (HR = 1.23; 1.04-1.44), in never HRT users (HR = 1.40; 1.16-1.68) and in oestrogen-and-progesterone-receptor-positive (ER+PR+) breast cancer (HR = 1.46; 1.15-1.85).

Conclusion: Long-term weight gain was positively associated with postmenopausal breast cancer in women who were lean at age 20, both in HRT ever users and non-users, and hormone-receptor-positive breast cancer.
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http://dx.doi.org/10.1093/ije/dyab032DOI Listing
March 2021

Red Blood Cell Fatty Acids and Risk of Colorectal Cancer in The European Prospective Investigation into Cancer and Nutrition (EPIC).

Cancer Epidemiol Biomarkers Prev 2021 05 22;30(5):874-885. Epub 2021 Feb 22.

Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Background: A growing body of evidence suggests that alterations of dietary fatty acid (FA) profiles are associated with colorectal cancer risk. However, data from large-scale epidemiologic studies using circulating FA measurements to objectively assess individual FA and FA categories are scarce.

Methods: We investigate the association between red blood cell (RBC) membrane FAs and risk of colorectal cancer in a case-control study nested within a large prospective cohort. After a median follow-up of 6.4 years, 1,069 incident colorectal cancer cases were identified and matched to 1,069 controls among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). The FA composition of RBC phospholipids (in mol%) was analyzed by gas chromatography, and their association with risk of colorectal cancer was estimated by multivariable adjusted conditional logistic regression models.

Results: After correction for multiple testing, subjects with higher concentrations of RBC stearic acid were at higher risk for colorectal cancer (OR = 1.23; 95% CI = 1.07-1.42, per 1 mol%). Conversely, colorectal cancer incidence decreased with increasing proportions of RBC n-3 PUFA, particularly eicosapentaenoic acid (0.75; 0.62-0.92, per 1 mol%). The findings for the n-6 PUFA arachidonic acid were inconsistent.

Conclusions: The positive association between prediagnostic RBC stearic acid and colorectal cancer reflects putative differences in FA intake and metabolism between cancer cases and matched controls, which deserve further investigation. The inverse relationship between EPA and colorectal cancer is in line with the repeatedly reported protective effect of fish consumption on colorectal cancer risk.

Impact: These findings add to the evidence on colorectal cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1426DOI Listing
May 2021

Risk Prediction for Renal Cell Carcinoma: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Prospective Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 03 17;30(3):507-512. Epub 2020 Dec 17.

School of Public Health, Imperial College London, London, United Kingdom.

Background: Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives.

Methods: Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure.

Results: The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679-0.721]). Our model had slightly improved discrimination (0.714 [0.694-0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025.

Conclusions: Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population.

Impact: Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1438DOI Listing
March 2021

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.

PLoS Med 2020 10 16;17(10):e1003394. Epub 2020 Oct 16.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

Background: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis.

Methods And Findings: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities.

Conclusions: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.
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http://dx.doi.org/10.1371/journal.pmed.1003394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567390PMC
October 2020

Adiposity and the risk of rheumatoid arthritis: a systematic review and meta-analysis of cohort studies.

Sci Rep 2020 09 29;10(1):16006. Epub 2020 Sep 29.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St. Mary's Campus, Norfolk Place, Paddington, London, W2 1PG, UK.

Several studies have investigated associations between overweight/obesity and risk of developing rheumatoid arthritis, however, the evidence is not entirely consistent, and previous meta-analyses mainly included case-control studies, which can be affected by various biases. We therefore conducted a systematic review and meta-analysis of cohort studies on adiposity and risk of rheumatoid arthritis. Relevant studies were identified by searching PubMed and Embase databases. Random effects models were used to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) for rheumatoid arthritis in relation to different measures of adiposity. Thirteen cohort studies (10 publications) were included. The summary RR per 5 kg/m increase in body mass index (BMI) was 1.11 (95% CI 1.05-1.18, I = 50%), but the association was restricted to women (1.15, 95% CI 1.08-1.21, I = 17%) and not observed in men (0.89, 95% CI 0.73-1.09, I = 58%). The summary RR per 5 kg/m increment in BMI at age 18 years was 1.17 (95% CI 1.01-1.36, I = 26%, n = 3), and per 10 cm increase in waist circumference was 1.13 (95% CI 1.02-1.25, I = 44%, n = 2). Higher BMI in middle age, BMI at age 18 years, and waist circumference were associated with increased rheumatoid arthritis risk, suggesting adiposity could be targeted for primary prevention.
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http://dx.doi.org/10.1038/s41598-020-71676-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524740PMC
September 2020

Sleep duration and breast cancer incidence: results from the Million Women Study and meta-analysis of published prospective studies.

Sleep 2021 02;44(2)

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Study Objectives: To investigate the association between sleep duration and breast cancer incidence, we examined the association in a large UK prospective study and conducted a meta-analysis of prospective studies.

Methods: In the Million Women Study, usual sleep duration over a 24-h period was collected in 2001 for 713,150 participants without prior cancer, heart problems, stroke, or diabetes (mean age = 60 years). Follow-up for breast cancer was by record linkage to national cancer registry data for 14.3 years on average from the 3-year resurvey. Cox regression models yielded multivariable-adjusted breast cancer relative risks (RR) and 95% confidence intervals (CIs) for sleep duration categories. Published prospective studies of sleep duration and breast cancer risk were included in a meta-analysis, which estimated the inverse-variance weighted average of study-specific log RRs for short and for long versus average duration sleep.

Results: After excluding the first 5 years to minimize reverse causation bias in the Million Women Study, 24,476 women developed breast cancer. Compared with 7-8 h of sleep, the RRs for <6, 6, 9, and >9 h of sleep were 1.01 (95% CI, 0.95-1.07), 0.99 (0.96-1.03), 1.01 (0.96-1.06), and 1.03 (0.95-1.12), respectively. In a meta-analysis of 14 prospective studies plus the Million Women Study, including 65,410 breast cancer cases, neither short (RR < 7 h = 0.99 [0.98-1.01]) nor long (RR > 8 h = 1.01 [0.98-1.04]) versus average duration sleep was associated with breast cancer risk.

Conclusions: The totality of the prospective evidence does not support an association between sleep duration and breast cancer risk.
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http://dx.doi.org/10.1093/sleep/zsaa166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879408PMC
February 2021

Replacement of Red and Processed Meat With Other Food Sources of Protein and the Risk of Type 2 Diabetes in European Populations: The EPIC-InterAct Study.

Diabetes Care 2020 11 31;43(11):2660-2667. Epub 2020 Aug 31.

CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Objective: There is sparse evidence for the association of suitable food substitutions for red and processed meat on the risk of type 2 diabetes. We modeled the association between replacing red and processed meat with other protein sources and the risk of type 2 diabetes and estimated its population impact.

Research Design And Methods: The European Prospective Investigation into Cancer (EPIC)-InterAct case cohort included 11,741 individuals with type 2 diabetes and a subcohort of 15,450 participants in eight countries. We modeled the replacement of self-reported red and processed meat with poultry, fish, eggs, legumes, cheese, cereals, yogurt, milk, and nuts. Country-specific hazard ratios (HRs) for incident type 2 diabetes were estimated by Prentice-weighted Cox regression and pooled using random-effects meta-analysis.

Results: There was a lower hazard for type 2 diabetes for the modeled replacement of red and processed meat (50 g/day) with cheese (HR 0.90, 95% CI 0.83-0.97) (30 g/day), yogurt (0.90, 0.86-0.95) (70 g/day), nuts (0.90, 0.84-0.96) (10 g/day), or cereals (0.92, 0.88-0.96) (30 g/day) but not for replacements with poultry, fish, eggs, legumes, or milk. If a causal association is assumed, replacing red and processed meat with cheese, yogurt, or nuts could prevent 8.8%, 8.3%, or 7.5%, respectively, of new cases of type 2 diabetes.

Conclusions: Replacement of red and processed meat with cheese, yogurt, nuts, or cereals was associated with a lower rate of type 2 diabetes. Substituting red and processed meat by other protein sources may contribute to the prevention of incident type 2 diabetes in European populations.
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http://dx.doi.org/10.2337/dc20-1038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576430PMC
November 2020

Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common, inherited vitamin D-binding protein isoforms.

Int J Cancer 2020 11 25;147(10):2725-2734. Epub 2020 May 25.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

Lower prediagnostic circulating 25-hydroxyvitamin D (25[OH]D)-considered the best marker of total vitamin D exposure-is associated with higher mortality risk among colorectal cancer (CRC) patients. However, it is unknown whether this association differs by the vitamin D-binding protein (GC) isoform Gc2 (encoded by GC rs4588*C>A, Thr436Lys), which may substantially affect vitamin D metabolism and modify associations of 25(OH)D with colorectal neoplasm risk. Prediagnostic 25(OH)D-mortality associations according to Gc2 isoform were estimated using multivariable Cox proportional hazards regression among 1281 CRC cases (635 deaths, 483 from CRC) from two large prospective cohorts conducted in the United States (Cancer Prevention Study-II) and Europe (European Prospective Investigation into Cancer and Nutrition). 25(OH)D measurements were calibrated to a single assay, season standardized, and categorized using Institute of Medicine recommendations (deficient [<30], insufficient [30 - <50], sufficient [≥50 nmol/L]). In the pooled analysis, multivariable-adjusted hazard ratios (HRs) for CRC-specific mortality associated with deficient relative to sufficient 25(OH)D concentrations were 2.24 (95% CI 1.44-3.49) among cases with the Gc2 isoform, and 0.94 (95% CI 0.68-1.22) among cases without Gc2 (P = .0002). The corresponding HRs for all-cause mortality were 1.80 (95% CI 1.24-2.60) among those with Gc2, and 1.12 (95% CI 0.84-1.51) among those without Gc2 (P = .004). Our findings suggest that the association of prediagnostic vitamin D status with mortality among CRC patients may differ by functional GC isoforms, and patients who inherit the Gc2 isoform (GC rs4588*A) may particularly benefit from higher circulating 25(OH)D for improved CRC prognosis.
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http://dx.doi.org/10.1002/ijc.33043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529852PMC
November 2020

Antibody Responses to and Risk of Developing Colorectal Cancer in a European Cohort.

Cancer Epidemiol Biomarkers Prev 2020 07 24;29(7):1475-1481. Epub 2020 Apr 24.

CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: While () is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Methods: We applied multiplex serology to measure antibody responses to 13 proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of overall and protein-specific seropositivity with odds of developing colorectal cancer.

Results: Fifty-one percent of colorectal cancer cases were seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00-1.85). Among the 13 individual proteins, the association was driven mostly by seropositivity to cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19-2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99-1.82), the latter being nonstatistically significant only in the fully adjusted model.

Conclusions: In this prospective multicenter European study, antibody responses to proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer.

Impact: Biological mechanisms for a potential causal role of in colorectal carcinogenesis need to be elucidated, and subsequently whether eradication may decrease colorectal cancer incidence.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1545DOI Listing
July 2020

Components of one-carbon metabolism and renal cell carcinoma: a systematic review and meta-analysis.

Eur J Nutr 2020 Dec 11;59(8):3801-3813. Epub 2020 Mar 11.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Purpose: Little is known about the aetiology of renal cell carcinoma (RCC). Components of one-carbon (1C) metabolism, which are required for nucleotide synthesis and methylation reactions, may be related to risk of RCC but existing evidence is inconclusive. We conducted a systematic review and independent exposure-specific meta-analyses of dietary intake and circulating biomarkers of 1C metabolites and RCC risk.

Methods: Medline and Embase databases were searched for observational studies investigating RCC or kidney cancer incidence or mortality in relation to components of 1C metabolism and 12 eligible articles were included in the meta-analyses. We used Bayesian meta-analyses to estimate summary relative risks (RRs) and 95% credible intervals (CrIs) comparing the highest versus lowest categories as well as the between-study heterogeneity.

Results: We did not find convincing evidence of an association between any exposure (riboflavin, vitamin B, folate, vitamin B, methionine, homocysteine, choline, or betaine) and RCC risk. However, vitamin B biomarker status did have a protective (RR = 0.62) but imprecise (95% CrI 0.39-1.14) effect estimate and folate intake had a notable association as well (RR = 0.85, 95% CrI 0.71-1.01).

Conclusion: There was a lack of precision due largely to the low number of studies. Further investigation is warranted, especially for folate and vitamin B, which had consistent suggestive evidence of a protective effect for both dietary intake and biomarker status. A unique strength of this review is the use of Bayesian meta-analyses which allowed for robust estimation of between-study heterogeneity.
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http://dx.doi.org/10.1007/s00394-020-02211-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669778PMC
December 2020

Circulating 25-hydroxyvitamin D concentration and cause-specific mortality in the Melbourne Collaborative Cohort Study.

J Steroid Biochem Mol Biol 2020 04 30;198:105612. Epub 2020 Jan 30.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia; Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

Vitamin D deficiency is associated with higher all-cause mortality, but associations with specific causes of death are unclear. We investigated the association between circulating 25-hydroxyvitamin D (25(OH)D) concentration and cause-specific mortality using a case-cohort study within the Melbourne Collaborative Cohort Study (MCCS). Eligibility for the case-cohort study was restricted to participants with baseline dried blood spot samples and no pre-baseline diagnosis of cancer. These analyses included participants who died (n = 2307) during a mean follow-up of 14 years and a sex-stratified random sample of eligible cohort participants ('subcohort', n = 2923). Concentration of 25(OH)D was measured using liquid chromatography-tandem mass spectrometry. Cox regression, with Barlow weights and robust standard errors to account for the case-cohort design, was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cause-specific mortality in relation to 25(OH)D concentration with adjustment for confounders. Circulating 25(OH)D concentration was inversely associated with risk of death due to cancer (HR per 25 nmol/L increment = 0.88, 95 % CI 0.78-0.99), particularly colorectal cancer (HR = 0.75, 95 % CI 0.57-0.99). Higher 25(OH)D concentrations were also associated with a lower risk of death due to diseases of the respiratory system (HR = 0.62, 95 % CI 0.43-0.88), particularly chronic obstructive pulmonary disease (HR = 0.53, 95 % CI 0.30-0.94), and diseases of the digestive system (HR = 0.44, 95 % CI 0.26-0.76). Estimates for diabetes mortality (HR = 0.64, 95 % CI 0.33-1.26) and cardiovascular disease mortality (HR = 0.90, 95 % CI 0.76-1.07) lacked precision. The findings suggest that vitamin D might be important for preventing death due to some cancers, respiratory diseases, and digestive diseases.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105612DOI Listing
April 2020

Nutrient-wide association study of 92 foods and nutrients and breast cancer risk.

Breast Cancer Res 2020 01 13;22(1). Epub 2020 Jan 13.

Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Several dietary factors have been reported to be associated with risk of breast cancer, but to date, unequivocal evidence only exists for alcohol consumption. We sought to systematically assess the association between intake of 92 foods and nutrients and breast cancer risk using a nutrient-wide association study.

Methods: Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression was used to quantify the association between each food/nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to be replicated in the independent Netherlands Cohort Study (NLCS).

Results: Six foods and nutrients were identified as associated with risk of breast cancer in the EPIC study (10,979 cases). Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake = 1.05, 95% CI 1.03-1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment = 1.05, 95% CI 1.03-1.06 and 1.04, 95% CI 1.02-1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment = 0.96, 95% CI 0.94-0.98; 0.96, 95% CI 0.94-0.99; and 0.96, 95% CI 0.95-0.98, respectively). When evaluated in the NLCS (2368 cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk in the NLCS.

Conclusions: Our findings confirm a positive association of alcohol consumption and suggest an inverse association of dietary fibre and possibly fruit intake with breast cancer risk.
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http://dx.doi.org/10.1186/s13058-019-1244-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958698PMC
January 2020

Alcohol intake and Parkinson's disease risk in the million women study.

Mov Disord 2020 03 26;35(3):443-449. Epub 2019 Nov 26.

Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Background: Alcohol intake may be associated with a lower risk of Parkinson's disease (PD), but findings from previous studies have been inconclusive.

Objective: To determine the association between alcohol intake and PD risk in the Million Women Study, a large, prospective study of women in the UK.

Methods: Between 1996 and 2001, approximately 1.3 million women in the UK, mean age 56 (standard deviation, 5) years, were recruited into the Million Women Study. Information on alcohol intake, lifestyle factors, and medical history was collected at recruitment by questionnaire. Information on incident cases of PD was ascertained by record linkage to national hospital admission records and death registrations. We estimated multivariable-adjusted relative risks and corresponding 95% confidence intervals using Cox proportional hazards models according to categories of alcohol intake.

Results: During an average of 17.9 years of follow-up, 11,009 women had a new record of PD among 1,309,267 women. In drinkers, the multivariable-adjusted relative risk comparing women who drank more than 14 drinks of alcohol per week with women who drank 1 to 2 drinks of alcohol per week was 0.99 (95% confidence interval: 0.90, 1.10). Results did not materially change after excluding the first 10 years of follow-up (relative risk = 1.01; 95% confidence interval: 0.90, 1.13). There were no significant trends in alcohol-related PD risk among never smokers. Additionally, examining this association by type of alcohol intake also yielded null findings.

Conclusion: These results do not support an association between alcohol intake and PD risk in women. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155013PMC
March 2020

Association Between Soft Drink Consumption and Mortality in 10 European Countries.

JAMA Intern Med 2019 Nov;179(11):1479-1490

Hellenic Health Foundation, Athens, Greece.

Importance: Soft drinks are frequently consumed, but whether this consumption is associated with mortality risk is unknown and has been understudied in European populations to date.

Objective: To examine the association between total, sugar-sweetened, and artificially sweetened soft drink consumption and subsequent total and cause-specific mortality.

Design, Setting, And Participants: This population-based cohort study involved participants (n = 451 743 of the full cohort) in the European Prospective Investigation into Cancer and Nutrition (EPIC), an ongoing, large multinational cohort of people from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom), with participants recruited between January 1, 1992, and December 31, 2000. Excluded participants were those who reported cancer, heart disease, stroke, or diabetes at baseline; those with implausible dietary intake data; and those with missing soft drink consumption or follow-up information. Data analyses were performed from February 1, 2018, to October 1, 2018.

Exposure: Consumption of total, sugar-sweetened, and artificially sweetened soft drinks.

Main Outcomes And Measures: Total mortality and cause-specific mortality. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazards regression models adjusted for other mortality risk factors.

Results: In total, 521 330 individuals were enrolled. Of this total, 451 743 (86.7%) were included in the study, with a mean (SD) age of 50.8 (9.8) years and with 321 081 women (71.1%). During a mean (range) follow-up of 16.4 (11.1 in Greece to 19.2 in France) years, 41 693 deaths occurred. Higher all-cause mortality was found among participants who consumed 2 or more glasses per day (vs consumers of <1 glass per month) of total soft drinks (hazard ratio [HR], 1.17; 95% CI, 1.11-1.22; P < .001), sugar-sweetened soft drinks (HR, 1.08; 95% CI, 1.01-1.16; P = .004), and artificially sweetened soft drinks (HR, 1.26; 95% CI, 1.16-1.35; P < .001). Positive associations were also observed between artificially sweetened soft drinks and deaths from circulatory diseases (≥2 glasses per day vs <1 glass per month; HR, 1.52; 95% CI, 1.30-1.78; P < .001) and between sugar-sweetened soft drinks and deaths from digestive diseases (≥1 glass per day vs <1 glass per month; HR, 1.59; 95% CI, 1.24-2.05; P < .001).

Conclusions And Relevance: This study found that consumption of total, sugar-sweetened, and artificially sweetened soft drinks was positively associated with all-cause deaths in this large European cohort; the results are supportive of public health campaigns aimed at limiting the consumption of soft drinks.
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http://dx.doi.org/10.1001/jamainternmed.2019.2478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724165PMC
November 2019

Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study.

J Natl Cancer Inst 2020 05;112(5):516-524

Hellenic Health Foundation, Athens, Greece.

Background: Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans.

Methods: Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations.

Results: Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95% CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk.

Conclusions: This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive.
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http://dx.doi.org/10.1093/jnci/djz166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225675PMC
May 2020

Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations.

Nutrients 2019 08 20;11(8). Epub 2019 Aug 20.

CIBER Epidemiology and Public Healh (CIBERESP), Madrid 28029, Spain.

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the , , and genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (, and ). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk ( ≤ 0.001), with most statistically significant genes being = 0.008) and = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites ( = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.
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http://dx.doi.org/10.3390/nu11081954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722852PMC
August 2019
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