Investigation of common genetic risk factors between thyroid traits and breast cancer.

Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 × 10-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 × 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 × 10-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 × 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 × 10-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.

Long-term exposure to air pollution and incidence of gastric and the upper aerodigestive tract cancers in a pooled European cohort: The ELAPSE project.

Air pollution has been shown to significantly impact human health including cancer. Gastric and upper aerodigestive tract (UADT) cancers are common and increased risk has been associated with smoking and occupational exposures. However, the association with air pollution remains unclear. We pooled European subcohorts (N = 287,576 participants for gastric and N = 297,406 for UADT analyses) and investigated the association between residential exposure to fine particles (PM2.5), nitrogen dioxide (NO2), black carbon (BC) and ozone in the warm season (O3w) with gastric and UADT cancer. We applied Cox proportional hazards models adjusting for potential confounders at the individual and area-level. During 5,305,133 and 5,434,843 person-years, 872 gastric and 1139 UADT incident cancer cases were observed, respectively. For gastric cancer, we found no association with PM2.5, NO2 and BC while for UADT the hazard ratios (95% confidence interval) were 1.15 (95% CI: 1.00-1.33) per 5 µg/m3 increase in PM2.5, 1.19 (1.08-1.30) per 10 µg/m3 increase in NO2, 1.14 (1.04-1.26) per 0.5 × 10-5 m-1 increase in BC and 0.81 (0.72-0.92) per 10 µg/m3 increase in O3w. We found no association between long-term ambient air pollution exposure and incidence of gastric cancer, while for long-term exposure to PM2.5, NO2 and BC increased incidence of UADT cancer was observed.

Pre-diagnostic circulating resistin concentrations and mortality among individuals with colorectal cancer: Results from the European Prospective Investigation into Cancer and Nutrition study.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HRQ4vsQ1 = 0.95, 95% CI: 0.73-1.23; Ptrend = .97; and HRper doubling of resistin concentration = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

Educational level and characteristics of invasive breast cancer: findings from a French prospective cohort.

PURPOSE: Breast cancer (BC) characteristics are known to influence patients survival. Social differences have been reported by previous studies for those characteristics but questions persist because of inconsistent conclusions. We aimed to investigate the impact of education on BC stage, grade, and hormone receptor (HR) status, while adjusting for potential confounders including a broad set of health behaviors, anthropometric measures, and reproductive factors. METHODS: In the French E3N cohort, 5236 women developed a primary invasive BC for which there was available information on stage, grade, and HR status. No multivariate analyses was performed for BC stage based on the lack of association in bivariate analyses. Odds ratios and confidence intervals were estimated using multinomial logistic regression models for BC grade or binomial logistic regression models for HR status of BC. RESULTS: Women with a lower education were diagnosed with higher grade BC compared to women with a higher education (1.32 [1.12; 1.57]). This association was slightly attenuated after adjustment for covariates independently and more strongly affected in the fully adjusted model (1.20 [0.99; 1.45]). A significant association was observed between lower education and HR- status of BC (1.20 [1.02; 1.42]) attenuated after adjustment for age at first childbirth (1.12 [0.95; 1.33]). CONCLUSION: In this cohort, education was associated with BC grade and HR status but not stage at diagnosis. The link between education and BC grade was not entirely explained by the different adjustments. A specific mechanism could be at play and deserves further investigations.

Depression and anxiety before and at the beginning of the COVID-19 pandemic and incident persistent symptoms: a prospective population-based cohort study.

Many patients affected by COVID-19 suffer from debilitating persistent symptoms whose risk factors remained poorly understood. This prospective study examined the association of depression and anxiety symptoms measured before and at the beginning of the COVID-19 pandemic with the incidence of persistent symptoms. Among 25,114 participants [mean (SD) age, 48.72 years (12.82); 51.1% women] from the SAPRIS and SAPRIS-Sérologie surveys nested in the French CONSTANCES population-based cohort, depression and anxiety symptoms were measured with the Center for Epidemiologic Studies-Depression scale and the 12-item General Health Questionnaire before the pandemic, and with the 9-item Patient Health Questionnaire and the 7-Item Generalized Anxiety Disorder scale at the beginning of the pandemic (i.e., between April 6, 2020 and May 4, 2020). Incident persistent symptoms were self-reported between December 2020 and January 2021. The following variables were also considered: gender, age, educational level, household income, smoking status, BMI, hypertension, diabetes, self-rated health, and SARS-CoV-2 infection according to serology/PCR test results. After a follow-up of seven to ten months, 2329 participants (9.3%) had been infected with SARS-CoV-2 and 4262 (17.0%) reported at least one incident persistent symptom that emerged from March 2020, regardless of SARS-CoV-2 infection. In multi-adjusted logistic regression models, participants in the highest (versus the lowest) quartile of depressive or anxiety symptom levels before or at the beginning of the pandemic were more likely to have at least one incident persistent symptom (versus none) at follow-up [OR (95%CI) ranging from 2.10 (1.89-2.32) to 3.01 (2.68-3.37)], with dose-response relationships (p for linear trend <0.001). Overall, these associations were significantly stronger in non-infected versus infected participants, except for depressive symptoms at the beginning of the pandemic. Depressive symptoms at the beginning of the pandemic were the strongest predictor of incident persistent symptoms in both infected and non-infected participants [OR (95%CI): 2.88 (2.01-4.14) and 3.03 (2.69-3.42), respectively]. In exploratory analyses, similar associations were found for each symptom taken separately in different models. Depression and anxiety symptoms should be tested as a potential target for preventive interventions against persistent symptoms after an infection with SARS-CoV-2.

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

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

Reproductive characteristics, use of exogenous hormones and Parkinson disease in women from the E3N study.

Despite experimental studies suggesting a disease-modifying role of oestrogens, results from epidemiological studies on the relation of reproductive characteristics and hormonal exposures with Parkinson disease in women are conflicting. We used the data from the E3N cohort study including 98 068 women aged 40-65 years in 1990 followed until 2018. Parkinson disease was ascertained using a validation process based on drug claim databases and medical records. Reproductive characteristics and hormonal exposures were self-reported (11 questionnaires). Associations of exposures with Parkinson disease incidence were investigated using time-varying Cox proportional hazards regression with a 5-year exposure lag and age as the timescale adjusted for confounders. We identified 1165 incident Parkinson disease cases during a mean follow-up of 22.0 years (incidence rate = 54.7 per 100 000 person-years). Parkinson disease incidence was higher in women with early (<12 years, HR = 1.21, 95% CI = 1.04-1.40) or late age at menarche (≥14 years, HR = 1.18, 95% CI = 1.03-1.35) than in women with menarche at 12-13 years. Nulliparity was not associated with Parkinson disease, but Parkinson disease incidence increased with the number of children in parous women (P-trend = 0.009). Women with artificial (surgical, iatrogenic) menopause were at greater risk than women with natural menopause (HR = 1.28, 95% CI = 1.09-1.47), especially when artificial menopause occurred at an early age (≤45.0 years). Postmenopausal hormone therapy tended to mitigate greater risk associated with artificial or early menopause (≤45.0 years). While fertility treatments were not associated with Parkinson disease overall, ever users of clomiphene were at greater Parkinson disease risk than never users (HR = 1.81, 95% CI = 1.14-2.88). Other exposures (breastfeeding, oral contraceptives) were not associated with Parkinson disease. Our findings suggest that early and late age at menarche, higher parity, and artificial menopause, in particular at an early age, are associated with increased Parkinson disease incidence in women. In addition, there was some evidence that use of exogenous hormones may increase (fertility treatments) or decrease (postmenopausal hormone therapy) Parkinson disease incidence. These findings support the hypothesis that hormonal exposures play a role in the susceptibility to neurodegenerative diseases. If confirmed, they could help to identify subgroups at high risk for Parkinson disease.

Macronutrient composition of plant-based diets and breast cancer risk: the E3N prospective cohort study.

PURPOSE: Recent evidence suggests that plant-based diets may reduce the risk of breast cancer (BC). However, the macronutrient composition of plant-based diets and its potential impact on BC risk has not been well explored. This analysis investigated the association of macronutrient composition with BC risk across a spectrum of plant-based diet indexes using a multidimensional approach. DESIGN: This study followed 64,655 participants from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (E3N) cohort from 1993 to 2014. Diets were evaluated using validated 208-item diet history questionnaires at baseline (1993) and follow-up (2005), to calculate adherence to the overall plant-based diet (PDI), healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI). The association of macronutrient composition with BC risk was assessed via generalized additive time-dependent Cox models across different levels of these indexes. Response surfaces were generated to visualize compositional associations at the 25th, 50th, and 75th percentile of each index (low, moderate, and high). RESULTS: A total of 3,932 incident BC cases were identified during the 21-year follow-up. There was a significant association between macronutrient composition and BC risk for hPDI, uPDI, and PDI (all P < 0.001). Akaike information criterion favored the hPDI model for characterizing the association between macronutrients and BC. BC risk was highest for individuals with a lower hPDI score who also consumed a diet containing lower protein (10%), lower carbohydrate (35%), and higher fat (55%). The lowest risk of BC was observed in those with higher hPDI scores with the lowest intake of protein (10%). At higher PDI and uPDI, diets containing higher protein (30%) and fat (45%) had the highest BC risk. CONCLUSION: These results demonstrate a complex relationship between macronutrient composition, plant-based diet quality, and BC risk. Further research is needed to examine specific foods that may be driving these associations. REGISTRY: The protocol is registered at clinicaltrials.gov as NCT03285230.

Blood levels of persistent organic pollutants among women in France in the 90's: Main profiles and individual determinants.

CONTEXT AND OBJECTIVES: Persistent organic pollutants (POPs) are a group of organic chemical compounds potentially toxic to human health. The objectives of this study were 1) to describe the levels of POPs biomarkers in blood samples from French women collected during the 1990s and to compare them with levels measured in two more recent French studies, 2) to identify POPs exposure profiles, and 3) to explore their main determinants. METHODS: 73 POPs biomarkers were measured in the blood of 468 women from the French E3N cohort (aged 45-73 years), collected between 1994 and 1999: 28 per- and polyfluoroalkyl substances, 27 organochlorine pesticides, 14 polychlorinated biphenyls and 4 polybrominated diphenyl ethers. POPs biomarker levels were described and compared with levels measured in two more recent French studies conducted by the French National Public Health Agency, the ENNS and Esteban studies. Principal component analysis was performed on POPs quantified in at least 75% of samples to identify the main exposure profiles. Linear regression models were used to estimate the associations between anthropometric, socio-demographic and lifestyle characteristics and exposure to these profiles. RESULTS: Among the 73 biomarkers measured, 41 were quantified in more than 75% of samples. Levels of most pollutants that were also measured in the Esteban of ENNS studies have decreased over time. Six POPs exposure profiles were revealed, explaining 62.1% of the total variance. Most of the characteristics studied were associated with adherence to at least one of these profiles. CONCLUSION: This study highlighted that most of the pollutants for which a comparison was possible decreased over the 10 or 20 years following the E3N blood collection, and identified those which, on the contrary, tended to increase. The health effects of the profiles identified could be assessed in future studies. The determinants identified should be confirmed in larger populations.

Long-term exposure to air pollution and chronic kidney disease-associated mortality-Results from the pooled cohort of the European multicentre ELAPSE-study.

Despite the known link between air pollution and cause-specific mortality, its relation to chronic kidney disease (CKD)-associated mortality is understudied. Therefore, we investigated the association between long-term exposure to air pollution and CKD-related mortality in a large multicentre population-based European cohort. Cohort data were linked to local mortality registry data. CKD-death was defined as ICD10 codes N18-N19 or corresponding ICD9 codes. Mean annual exposure at participant's home address was determined with fine spatial resolution exposure models for nitrogen dioxide (NO2), black carbon (BC), ozone (O3), particulate matter ≤2.5 µm (PM2.5) and several elemental constituents of PM2.5. Cox regression models were adjusted for age, sex, cohort, calendar year of recruitment, smoking status, marital status, employment status and neighbourhood mean income. Over a mean follow-up time of 20.4 years, 313 of 289,564 persons died from CKD. Associations were positive for PM2.5 (hazard ratio (HR) with 95% confidence interval (CI) of 1.31 (1.03-1.66) per 5 µg/m3, BC (1.26 (1.03-1.53) per 0.5 × 10- 5/m), NO2 (1.13 (0.93-1.38) per 10 µg/m3) and inverse for O3 (0.71 (0.54-0.93) per 10 µg/m3). Results were robust to further covariate adjustment. Exclusion of the largest sub-cohort contributing 226 cases, led to null associations. Among the elemental constituents, Cu, Fe, K, Ni, S and Zn, representing different sources including traffic, biomass and oil burning and secondary pollutants, were associated with CKD-related mortality. In conclusion, our results suggest an association between air pollution from different sources and CKD-related mortality.

Methylation scores for smoking, alcohol consumption and body mass index and risk of seven types of cancer.

Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values. Rate ratios (RR) and 95% confidence intervals for association with cancer risk were estimated using conditional logistic regression and expressed per SD increase of the MS, with and without adjustment for health-related confounders. The contribution of MS to discriminate cases from controls was evaluated using the area under the curve (AUC). After confounder adjustment, we observed: large associations (RR = 1.5-1.7) with lung cancer risk for smoking MS; moderate associations (RR = 1.2-1.3) with urothelial cancer risk for smoking MS and with mature B-cell neoplasm risk for BMI and alcohol MS; moderate to small associations (RR = 1.1-1.2) for BMI and alcohol MS with several cancer types and cancer overall. Generally small AUC increases were observed after inclusion of several MS in the same model (colorectal, gastric, kidney, urothelial cancers: +3%; lung cancer: +7%; B-cell neoplasms: +8%). Methylation scores for smoking, BMI and alcohol consumption show independent associations with cancer risk, and may provide some improvements in risk prediction.

Blood cell DNA methylation biomarkers in preclinical malignant pleural mesothelioma: The EPIC prospective cohort.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive noninvasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM prediagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow-up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within 5 years from enrolment (n = 36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex and PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than 5 years before diagnosis (area under the curve [AUC] < 5 years = 0.89; AUC 5-10 years = 0.80; AUC >10 years = 0.75; baseline AUC range = 0.63-0.67). DNAm changes as noninvasive biomarkers in prediagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk to possibly adopt more intensive monitoring for early disease identification.

Baseline and lifetime alcohol consumption and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend  = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend  = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend  = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend  = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17, Ptrend  = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend  = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend  = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; Ptrend  = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer.

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

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

Dietary intake of total, heme and non-heme iron and the risk of colorectal cancer in a European prospective cohort study.

BACKGROUND: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive. METHODS: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method. RESULTS: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HRQ5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HRQ5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HRQ5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HRQ5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HRQ5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HRQ5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). CONCLUSIONS: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources.

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

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

Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts.

BACKGROUND: Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS: Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases. RESULTS: Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded. CONCLUSIONS: Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.

Relative to processed red meat, alternative protein sources are associated with a lower risk of hypertension and diabetes in a prospective cohort of French women.

Many dietary guidelines recommend restricting the consumption of processed red meat (PRM) in favour of healthier foods such as fish, to reduce the risk of chronic conditions such as hypertension and diabetes. The objective of this study was to estimate the potential effect of replacing PRM for fatty fish, lean fish, red meat, eggs, pulses, or vegetables, on the risk of incident hypertension and diabetes. This was a prospective study of women in the E3N cohort study. Cases of diabetes and hypertension were based on self-report, specific questionnaires, and drug reimbursements. In the main analysis, information on regular dietary intake was assessed with a single food history questionaire, and food substitutions were modelled using cox proportional hazard models. 95 % confidence intervals were generated via bootstrapping. 71 081 women free of diabetes and 45 771 women free of hypertension were followed for an average of 18·7 and 18·3 years, respectively. 2681 incident cases of diabetes and 12 327 incident cases of hypertension were identified. Relative to PRM, fatty fish was associated with a 15 % lower risk of diabetes (HR = 0·85, 95 CI (0·73, 0·97)) and hypertension (HR = 0 85 (0·79, 0·91)). Between 3 and 10 % lower risk of hypertension or diabetes was also observed when comparing PRM with vegetables, unprocessed red meat or pulses. Relative to PRM, alternative protein sources such as fatty fish, unprocessed red meat, vegetables or pulses was associated with a lower risk of hypertension and diabetes.

Antibody response, associated symptoms and profile of patients presumably infected by SARS-CoV-2 with taste or smell disorders in the SAPRIS multicohort study.

BACKGROUND: Taste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and antibody response intensity associated with taste or smell disorders. METHODS: We used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave. RESULTS: The analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea. CONCLUSIONS: Among patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with an antibody response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.

Associations between saturated fat intake and other dietary macronutrients and incident hypertension in a prospective study of French women.

PURPOSE: Saturated fat has long been associated with cardiovascular disease in multiple prospective studies, and randomized controlled trials. Few studies have assessed the relative associations between saturated fat and other macronutrients with hypertension, a major risk factor for cardiovascular disease. The aim of this study was to assess the relative associations between saturated fat, other macronutrients such as monounsaturated and polyunsaturated fat, proteins, and carbohydrates, and incident hypertension in a large prospective cohort of French women. METHODS: This study used data from the E3N cohort study, including participants free of hypertension at baseline. A food frequency questionnaire was used to determine dietary intakes of saturated fat (SFA), monounsaturated fat (MUFA), polyunsaturated fat (PUFA), animal protein (AP), vegetable protein (VP), carbohydrates (CH) and various foods. Cases of hypertension were based on self-report, validated by drug reimbursement data. Covariates were based on self-report. Cox proportional hazard models were used to estimate the relative associations between different macronutrients and hypertension risk, using the 'substitution' framework. Bootstrapping was used to generate 95% confidence intervals. RESULTS: This study included 45,854 women free of hypertension at baseline. During 708,887 person-years of follow-up, 12,338 incident cases of hypertension were identified. Compared to saturated fat, higher consumption of all other macronutrients was associated with a lower risk of hypertension (HRMUFA = 0.74 [0.67: 0.81], HRPUFA = 0.84 [0.77: 0.92], HRCH = 0.83 [0.77: 0.88], HRAP = 0.91 [0.85: 0.97], HRVP = 0.93 [0.83: 1.03]). CONCLUSION: This study finds that relative to other macronutrients such as monounsaturated or polyunsaturated fat, higher intake of saturated fat is associated with a higher risk of hypertension among women.