Elena Molina-Portillo

Modifiable causes of premature death in middle-age in Western Europe: Results from the EPIC cohort study

BackgroundLife expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death.MethodsWe analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models.ResultsWe identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31–32 %) and 14 % (95 % CI, 12–16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8–12 %) and high blood pressure (9 %; 95 % CI, 7–11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55–59 %), being 35 % (95 % CI, 32–37 %) among never smokers and 74 % (95 % CI, 73–75 %) among current smokers.ConclusionsWhile smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed.

Parity, breastfeeding and risk of coronary heart disease: A pan-European case-cohort study

Objective There is uncertainty about the direction and magnitude of the associations between parity, breastfeeding and the risk of coronary heart disease (CHD). We examined the separate and combined associations of parity and breastfeeding practices with the incidence of CHD later in life among women in a large, pan-European cohort study. Methods Data were used from European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD, a case–cohort study nested within the EPIC prospective study of 520,000 participants from 10 countries. Information on reproductive history was available for 14,917 women, including 5138 incident cases of CHD. Using Prentice-weighted Cox regression separately for each country followed by a random-effects meta-analysis, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CHD, after adjustment for age, study centre and several socioeconomic and biological risk factors. Results Compared with nulliparous women, the adjusted HR was 1.19 (95% CI: 1.01–1.41) among parous women; HRs were higher among women with more children (e.g., adjusted HR: 1.95 (95% CI: 1.19–3.20) for women with five or more children). Compared with women who did not breastfeed, the adjusted HR was 0.71 (95% CI: 0.52–0.98) among women who breastfed. For childbearing women who never breastfed, the adjusted HR was 1.58 (95% CI: 1.09–2.30) compared with nulliparous women, whereas for childbearing women who breastfed, the adjusted HR was 1.19 (95% CI: 0.99–1.43). Conclusion Having more children was associated with a higher risk of CHD later in life, whereas breastfeeding was associated with a lower CHD risk. Women who both had children and breastfed did have a non-significantly higher risk of CHD.

Circulating copper and zinc levels and risk of hepatobiliary cancers in Europeans

Background:Copper and zinc are essential micronutrients and cofactors of many enzymatic reactions that may be involved in liver-cancer development. We aimed to assess pre-diagnostic circulating levels of copper, zinc and their ratio (Cu/Zn) in relation to hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBD) and gall bladder and biliary tract (GBTC) cancers.Methods:A nested case–control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. Serum zinc and copper levels were measured in baseline blood samples by total reflection X-ray fluorescence in cancer cases (HCC n=106, IHDB n=34, GBTC n=96) and their matched controls (1:1). The Cu/Zn ratio, an indicator of the balance between the micronutrients, was computed. Multivariable adjusted odds ratios and 95% confidence intervals (OR; 95% CI) were used to estimate cancer risk.Results:For HCC, the highest vs lowest tertile showed a strong inverse association for zinc (OR=0.36; 95% CI: 0.13–0.98, Ptrend=0.0123), but no association for copper (OR=1.06; 95% CI: 0.45–2.46, Ptrend=0.8878) in multivariable models. The calculated Cu/Zn ratio showed a positive association for HCC (OR=4.63; 95% CI: 1.41–15.27, Ptrend=0.0135). For IHBC and GBTC, no significant associations were observed.Conclusions:Zinc may have a role in preventing liver-cancer development, but this finding requires further investigation in other settings.

Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: A nested case-control study in nonsmoking postmenopausal women from the EPIC cohort

Acrylamide, classified in 1994 by IARC as “probably carcinogenic to humans,” was discovered in 2002 in some heat‐treated, carbohydrate‐rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case‐control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non‐smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type‐I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1: 0.84, 95%CI: 0.49–1.48; HRHbGA;Q5vsQ1: 0.94, 95%CI: 0.54–1.63) or type‐I EC risk. Additionally, none of the subgroups investigated (BMI < 25 vs. ≥25 kg m−2, alcohol drinkers vs. never drinkers, oral contraceptive users vs. non‐users) demonstrated effect measure modification. Hemoglobin adducts of acrylamide or glycidamide were not associated with EC or type‐I EC risk in 768 nonsmoking postmenopausal women from the EPIC cohort.

A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes : The EPIC-InterAct case-cohort study

Background Combinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated. Methods and findings We measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991–1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested case-cohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of γ-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19–0.29) adjusted for potential confounders and 0.37 (95% CI 0.27–0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0.05 each). Limitations include potential measurement error in the fatty acids and other model covariates and possible residual confounding. Conclusions A combination of individual fatty acids, characterised by high concentrations of linoleic acid, odd-chain fatty acids, and very long-chain fatty acids, was associated with lower incidence of T2D. The specific fatty acid pattern may be influenced by metabolic, genetic, and dietary factors.

The association between adult attained height and sitting height with mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Adult height and sitting height may reflect genetic and environmental factors, including early life nutrition, physical and social environments. Previous studies have reported divergent associations for height and chronic disease mortality, with positive associations observed for cancer mortality but inverse associations for circulatory disease mortality. Sitting height might be more strongly associated with insulin resistance; however, data on sitting height and mortality is sparse. Using the European Prospective Investigation into Cancer and Nutrition study, a prospective cohort of 409,748 individuals, we examined adult height and sitting height in relation to all-cause and cause-specific mortality. Height was measured in the majority of participants; sitting height was measured in ~253,000 participants. During an average of 12.5 years of follow-up, 29,810 deaths (11,931 from cancer and 7,346 from circulatory disease) were identified. Hazard ratios (HR) with 95% confidence intervals (CI) for death were calculated using multivariable Cox regression within quintiles of height. Height was positively associated with cancer mortality (men: HRQ5 vs. Q1 = 1.11, 95%CI = 1.00–1.24; women: HRQ5 vs. Q1 = 1.17, 95%CI = 1.07–1.28). In contrast, height was inversely associated with circulatory disease mortality (men: HRQ5 vs. Q1 = 0.63, 95%CI = 0.56–0.71; women: HRQ5 vs. Q1 = 0.81, 95%CI = 0.70–0.93). Although sitting height was not associated with cancer mortality, it was inversely associated with circulatory disease (men: HRQ5 vs. Q1 = 0.64, 95%CI = 0.55–0.75; women: HRQ5 vs. Q1 = 0.60, 95%CI = 0.49–0.74) and respiratory disease mortality (men: HRQ5 vs. Q1 = 0.45, 95%CI = 0.28–0.71; women: HRQ5 vs. Q1 = 0.60, 95%CI = 0.40–0.89). We observed opposing effects of height on cancer and circulatory disease mortality. Sitting height was inversely associated with circulatory disease and respiratory disease mortality.

Fruit and vegetable intake and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Several dietary factors have been studied in relation to prostate cancer; however, most studies have not reported on subtypes of fruit and vegetables or tumor characteristics, and results obtained so far are inconclusive. This study aimed to examine the prospective association of total and subtypes of fruit and vegetable intake with the incidence of prostate cancer overall, by grade and stage of disease, and prostate cancer death. Lifestyle information for 142,239 men participating in the European Prospective Investigation into Cancer and Nutrition from 8 European countries was collected at baseline. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average follow‐up time of 13.9 years, 7,036 prostate cancer cases were identified. Compared with the lowest fifth, those in the highest fifth of total fruit intake had a significantly reduced prostate cancer risk (HR = 0.91; 95% CI = 0.83–0.99; p‐trend = 0.01). No associations between fruit subtypes and prostate cancer risk were observed, except for citrus fruits, where a significant trend was found (HR = 0.94; 95% CI = 0.86–1.02; p‐trend = 0.01). No associations between total and subtypes of vegetables and prostate cancer risk were observed. We found no evidence of heterogeneity in these associations by tumor grade and stage, with the exception of significant heterogeneity by tumor grade (pheterogeneity<0.001) for leafy vegetables. No significant associations with prostate cancer death were observed. The main finding of this prospective study was that a higher fruit intake was associated with a small reduction in prostate cancer risk. Whether this association is causal remains unclear.

Standardizing effect size from linear regression models with log-transformed variables for meta-analysis

BackgroundMeta-analysis is very useful to summarize the effect of a treatment or a risk factor for a given disease. Often studies report results based on log-transformed variables in order to achieve the principal assumptions of a linear regression model. If this is the case for some, but not all studies, the effects need to be homogenized.MethodsWe derived a set of formulae to transform absolute changes into relative ones, and vice versa, to allow including all results in a meta-analysis. We applied our procedure to all possible combinations of log-transformed independent or dependent variables. We also evaluated it in a simulation based on two variables either normally or asymmetrically distributed.ResultsIn all the scenarios, and based on different change criteria, the effect size estimated by the derived set of formulae was equivalent to the real effect size. To avoid biased estimates of the effect, this procedure should be used with caution in the case of independent variables with asymmetric distributions that significantly differ from the normal distribution. We illustrate an application of this procedure by an application to a meta-analysis on the potential effects on neurodevelopment in children exposed to arsenic and manganese.ConclusionsThe procedure proposed has been shown to be valid and capable of expressing the effect size of a linear regression model based on different change criteria in the variables. Homogenizing the results from different studies beforehand allows them to be combined in a meta-analysis, independently of whether the transformations had been performed on the dependent and/or independent variables.

Association between plasma phospholipid saturated fatty acids and metabolic markers of lipid, hepatic, inflammation and glycaemic pathways in eight European countries : A cross-sectional analysis in the EPIC-InterAct study

BackgroundAccumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine the associations between plasma phospholipid SFAs and the metabolic markers of lipid, hepatic, glycaemic and inflammation pathways.MethodsWe measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0 + C17:0, even-chain: C14:0 + C16:0 + C18:0, and very-long-chain: C20:0 + C22:0 + C23:0 + C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across eight European countries. Using linear regression in 15,919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross-sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the three SFA groups with pre-specified factors, including body mass index (BMI) and alcohol consumption, were tested.ResultsHigher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol (TC), triglycerides, apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB)) and hepatic markers (alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT)). Higher even-chain SFA group levels were associated with higher levels of low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very-long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption.ConclusionsSubtypes of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk and even-chain SFAs with adverse metabolic risk, whereas mixed findings were obtained for very-long-chain SFAs. The clinical and biochemical implications of these findings may vary by adiposity and alcohol intake.

Circulating Metabolites Associated with Alcohol Intake in the European Prospective Investigation into Cancer and Nutrition Cohort

Identifying the metabolites associated with alcohol consumption may provide insights into the metabolic pathways through which alcohol may affect human health. We studied associations of alcohol consumption with circulating concentrations of 123 metabolites among 2974 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Alcohol consumption at recruitment was self-reported through dietary questionnaires. Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQTM p180 kit). Data were randomly divided into discovery (2/3) and replication (1/3) sets. Multivariable linear regression models were used to evaluate confounder-adjusted associations of alcohol consumption with metabolite concentrations. Metabolites significantly related to alcohol intake in the discovery set (FDR q-value < 0.05) were further tested in the replication set (Bonferroni-corrected p-value < 0.05). Of the 72 metabolites significantly related to alcohol intake in the discovery set, 34 were also significant in the replication analysis, including three acylcarnitines, the amino acid citrulline, four lysophosphatidylcholines, 13 diacylphosphatidylcholines, seven acyl-alkylphosphatidylcholines, and six sphingomyelins. Our results confirmed earlier findings that alcohol consumption was associated with several lipid metabolites, and possibly also with specific acylcarnitines and amino acids. This provides further leads for future research studies aiming at elucidating the mechanisms underlying the effects of alcohol in relation to morbid conditions.