Conflicting evidence exists regarding the association between saturated fatty acids (SFAs) and type 2 diabetes. In this longitudinal case-cohort study, we aimed to investigate the prospective ...associations between objectively measured individual plasma phospholipid SFAs and incident type 2 diabetes in EPIC-InterAct participants.
The EPIC-InterAct case-cohort study includes 12 403 people with incident type 2 diabetes and a representative subcohort of 16 154 individuals who were selected from a cohort of 340 234 European participants with 3·99 million person-years of follow-up (the EPIC study). Incident type 2 diabetes was ascertained until Dec 31, 2007, by a review of several sources of evidence. Gas chromatography was used to measure the distribution of fatty acids in plasma phospholipids (mol%); samples from people with type 2 diabetes and subcohort participants were processed in a random order by centre, and laboratory staff were masked to participant characteristics. We estimated country-specific hazard ratios (HRs) for associations per SD of each SFA with incident type 2 diabetes using Prentice-weighted Cox regression, which is weighted for case-cohort sampling, and pooled our findings using random-effects meta-analysis.
SFAs accounted for 46% of total plasma phospholipid fatty acids. In adjusted analyses, different individual SFAs were associated with incident type 2 diabetes in opposing directions. Even-chain SFAs that were measured (14:0 myristic acid, 16:0 palmitic acid, and 18:0 stearic acid) were positively associated with incident type 2 diabetes (HR 95% CI per SD difference: myristic acid 1·15 95% CI 1·09–1·22, palmitic acid 1·26 1·15–1·37, and stearic acid 1·06 1·00–1·13). By contrast, measured odd-chain SFAs (15:0 pentadecanoic acid and 17:0 heptadecanoic acid) were inversely associated with incident type 2 diabetes (HR 95% CI per 1 SD difference: 0·79 0·73–0·85 for pentadecanoic acid and 0·67 0·63–0·71 for heptadecanoic acid), as were measured longer-chain SFAs (20:0 arachidic acid, 22:0 behenic acid, 23:0 tricosanoic acid, and 24:0 lignoceric acid), with HRs ranging from 0·72 to 0·81 (95% CIs ranging between 0·61 and 0·92). Our findings were robust to a range of sensitivity analyses.
Different individual plasma phospholipid SFAs were associated with incident type 2 diabetes in opposite directions, which suggests that SFAs are not homogeneous in their effects. Our findings emphasise the importance of the recognition of subtypes of these fatty acids. An improved understanding of differences in sources of individual SFAs from dietary intake versus endogenous metabolism is needed.
EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.
Metabolic syndrome (defined as at least three among abdominal obesity, high blood triglycerides, low high-density lipoprotein cholesterol, high blood glucose, and high blood pressure) is emerging as ...a risk factor for breast cancer; however few studies - most confined to postmenopausal women - have investigated associations between breast cancer risk and metabolic syndrome. The purpose of this study was to examine the association between metabolic syndrome and its components, and risk of breast cancer in postmenopausal and premenopausal women.
We performed a case-cohort study on 22,494 women recruited in 1993-1998 to four Italian centres (Turin, Varese, Naples, Ragusa) of the European Prospective Investigation into Cancer and Nutrition (EPIC) and followed-up for up to 15 years. A random subcohort of 565 women was obtained and 593 breast cancer cases were diagnosed. Hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounders, were estimated by Prentice-weighted Cox proportional hazards models.
Presence of metabolic syndrome was associated with significantly increased breast cancer risk in all women (HR 1.52, 95%CI 1.14-2.02). When the analyses were repeated separately for menopausal status, the association was limited to postmenopausal women (HR 1.80, 95%CI 1.22-2.65) and absent in premenopausal women (HR 0.71, 95%CI 0.43-1.16); P for interaction between metabolic syndrome and menopausal status was 0.001. Of metabolic syndrome components, only high blood glucose was significantly associated with increased breast cancer risk in all women (HR 1.47, 95%CI 1.13-1.91) and postmenopausal women (HR 1.89, 95%CI 1.29-2.77), but not premenopausal women (HR 0.80, 95%CI 0.52-1.22; P interaction=0.004).
These findings support previous data indicating that metabolic syndrome is an important risk factor for breast cancer in postmenopausal women, but not in premenopausal women, and suggest that prevention of metabolic syndrome through lifestyle changes could confer protection against breast cancer.
Colorectal cancer is the third most common cancer worldwide. Diet has been hypothesized as involved in colorectal cancer etiology, but few studies on the influence of total dietary antioxidant intake ...on colorectal cancer risk have been performed.
We investigated the association between colorectal cancer risk and the total antioxidant capacity (TAC) of the diet, and also of intake of selected antioxidants, in 45,194 persons enrolled in 5 centers (Florence, Naples, Ragusa, Turin and Varese) of the European Prospective Investigation into Cancer and Nutrition (EPIC) Italy study. TAC was estimated by the Trolox equivalent antioxidant capacity (TEAC) assay. Hazard ratios (HRs) for developing colorectal cancer, and colon and rectal cancers separately, adjusted for confounders, were estimated for tertiles of TAC by Cox modeling, stratifying by center.
Four hundred thirty-six colorectal cancers were diagnosed over a mean follow-up of 11.28 years. No significant association between dietary TAC and colorectal cancer incidence was found. However for the highest category of TAC compared to the lowest, risk of developing colon cancer was lower (HR: 0.63; 95% CI: 0.44-0.89, P trend: 0.008). By contrast, increasing TAC intake was associated with significantly increasing risks of rectal cancer (2nd tertile HR: 2.09; 95%CI: 1.19-3.66; 3rd tertile 2.48 95%CI: 1.32-4.66; P trend 0.007). Intakes of vitamin C, vitamin E, and ß-carotene were not significantly associated with colorectal cancer risk.
Further prospective studies are needed to confirm the contrasting effects of high total antioxidant intake on risk of colon and rectal cancers.
In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of ...this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).
We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).
Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.
A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation ...after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case‐control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV‐2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead‐based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 95% CI = 1.22‐4.32). Positive serology for chlamydia heat shock protein 60 (cHSP60‐1) was associated with higher risk of EOC overall (1.36 1.13‐1.64) and with the serous subtype (1.44 1.12‐1.85). None of the other evaluated STIs were associated with EOC risk overall; however, HSV‐2 was associated with higher risk of endometrioid EOC (2.35 1.24‐4.43). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV‐2 might promote the development of endometrioid disease.
What's new?
Sexually transmitted infections (STI) have been linked with pelvic inflammatory disease but their association with ovarian cancer remains unclear. In this large prospective study, serum antibodies against Chlamydia trachomatis were associated with higher epithelial ovarian cancer risk, though some associations were limited to select histotypes. Herpes simplex virus type 2 infection was associated with endometrioid ovarian cancer, a rarer ovarian cancer subtype. These findings underscore that STIs may be important in the etiology of ovarian cancer and may represent a target for primary prevention.
Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack‐years and a dose‐response relationship with increasing pack‐years of smoking ...between menarche and first full‐term pregnancy (FFTP). Studies with comprehensive quantitative life‐time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) 95% confidence interval (CI) 1.16 1.05–1.28, 1.14 1.04–1.25 and 1.10 1.01–1.20, respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack‐years from menarche to FFTP (1.73 1.29–2.32 for every increase of 20 pack‐years) while pack‐years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34–0.82 for every increase of 20 pack‐years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious.
What's new?
The EPIC study is the largest cohort analysis on smoking and breast cancer to date. In this analysis of data from that study, the authors have confirmed that both active and passive exposure to cigarette smoke increases breast cancer risk. These results emphasize that it's important to distinguish between passive exposure and no exposure when analyzing the relationship between smoking and breast cancer. The authors also confirm that the most potent window of exposure for smoking and breast cancer risk is between menarche and first full term pregnancy.
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).
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.
After adjustment for body mass index, sphingomyelin SM C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05–1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80–0.99; OR1SD: 0.89, 95% CI: 0.79–1.00 and OR1SD: 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 (OR1SD: 1.14, 95% CI: 1.02–1.28) and that of short chain to free acylcarnitines (OR1SD: 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.
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.
•Endometrial cancer is the most common gynecological cancer in developed countries.•Metabolomics may uncover novel pathways linked to endometrial cancer.•853 endometrial cancer case-control pairs from EPIC underwent metabolomic profiling.•Specific amino acids, sphingolipids & carnitine were linked to endometrial cancer.•If causal, these pathways may offer novel targets for endometrial cancer prevention.
Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify ...the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI).
The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5-22.4 kg/m(2)) with a low WC (<94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI≥35 kg/m(2)) and a high WC (>102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50-103 per 1,000 person-years in men and 28-74 per 1,000 person-years in women).
WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action.
The relationship between coffee consumption and coronary heart disease (CHD) has been investigated in several studies with discrepant results. We examined the association between Italian-style ...(espresso and mocha) coffee consumption and CHD risk.
We investigated 12,800 men and 30,449 women without history of cardiovascular disease recruited to the EPICOR prospective cohort study. Coffee consumption was assessed at baseline. In a random sub-cohort of 1472 subjects, plasma triglycerides, and total, LDL and HDL cholesterol were determined to investigate the effect of coffee consumption on plasma lipids.
After a mean follow up of 10.9 years, 804 cases of CHD (500 acute events, 56 fatal events and 248 revascularizations, all first events) were identified. Multivariable adjusted hazard ratios for CHD were: 1.18 (95% CI 0.87-1.60) for drinking 1-2 cups/day, 1.37 (95% CI 1.03-1.82) for >2-4 cups/day and 1.52 (95% CI 1.11-2.07) for over 4 cups/day (P trend <0.001) compared to reference (<1 cup/day). Plasma triglycerides, and total, LDL and HDL cholesterol did not vary significantly (ANOVA) with coffee consumption.
Consumption of over 2 cups/day of Italian-style coffee is associated with increased CHD risk, but coffee consumption was not associated with plasma lipid changes, so the adverse effect of consumption appears unrelated to lipid profile.
Scope
The goal of this work is to identify circulating biomarkers of habitual coffee intake using a metabolomic approach, and to investigate their associations with coffee intake in four European ...countries.
Methods and results
Untargeted mass spectrometry‐based metabolic profiling is performed on serum samples from 451 participants of the European Prospective Investigation on Cancer and Nutrition (EPIC) originating from France, Germany, Greece, and Italy. Eleven coffee metabolites are found to be associated with self‐reported habitual coffee intake, including eight more strongly correlated (r = 0.25–0.51, p < 10E−07). Trigonelline shows the highest correlation, followed by caffeine, two caffeine metabolites (paraxanthine and 5‐Acetylamino‐6‐amino‐3‐methyluracil), quinic acid, and three compounds derived from coffee roasting (cyclo(prolyl‐valyl), cyclo(isoleucyl‐prolyl), cyclo(leucyl‐prolyl), and pyrocatechol sulfate). Differences in the magnitude of correlations are observed between countries, with trigonelline most highly correlated with coffee intake in France and Germany, quinic acid in Greece, and cyclo(isoleucyl‐prolyl) in Italy.
Conclusion
Several biomarkers of habitual coffee intake are identified. No unique biomarker is found to be optimal for all tested populations. Instead, optimal biomarkers are shown to depend on the population and on the type of coffee consumed. These biomarkers should help to further explore the role of coffee in disease risk.
Eleven metabolites measured in serum samples from 451 subjects of the European Prospective Investigation on Cancer and Nutrition (EPIC) study originating from France, Germany, Greece and Italy were found to be associated with coffee intake. They include trigonellline, caffeine and caffeine metabolites, quinic acid, and two diketopiperazines and catechol sulfate derived from coffee roasting. Variations in the magnitude of correlations and of ratios between metabolites indicate differences in the composition of coffee brews consumed by individuals from the four countries.
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