CRISPR/Cas9, the Powerful New Genome-Editing Tool for Putative Therapeutics in Obesity.

The molecular technology known as clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) is revolutionizing the field of medical research and deepening our understanding of numerous biological processes. The attraction of CRISPR/Cas9 lies in its ability to efficiently edit DNA or modulate gene expression in living eukaryotic cells and organisms, a technology that was once considered either too expensive or scientifically risky. CRISPR/Cas9 has been successfully applied in agriculture to develop the next generation of disease-resistant plants. Now, the capability of gene editing has been translated to the biomedical area, focusing on the future of medicine faced with drug-resistant microbes by selectively targeting genes involved in antibiotic resistance, for example, or finding the ultimate strategy for cancer or HIV. In this regard, it was recently demonstrated that an injection of cancer-fighting CRISPR-modified white blood cells in a patient suffering from metastatic lung cancer could lead to promising results. Researchers and bioethicists are debating questions about the regulation of CRISPR/Cas9 that must be addressed. While legal challenges surround the use of this technique for genetically modifying cell lines in humans, we review the basic understanding of CRISPR/Cas9 and discuss how this technology could represent a candidate for treatment of non-communicable diseases in nutrition, such as obesity.

Aromatic DNA adducts and breast cancer risk: a case-cohort study within the EPIC-Spain.

Epidemiologic evidence linking environmental exposure to polycyclic aromatic hydrocarbons (PAH) with breast cancer is limited. Measurement of DNA adducts formed by aromatic compounds, including PAH, has been carried in breast tissue samples and white blood cells from women with breast cancer and different kinds of controls. However, these studies provide inconsistent results and bias cannot be ruled out. During the 7-year follow-up period, 305 women were diagnosed with first primary breast cancer in the EPIC-Spain cohort, and were compared with a sample of 149 women without breast cancer at recruitment, using a case-cohort approach. Aromatic adducts to DNA from leukocytes collected at recruitment were measured by means of the 32P-post-labelling technique. The relative risk and 95% confidence interval (CI), adjusted by relevant confounders, were estimated by a modified version of Cox proportional hazards model. There was a significant increased risk for developing breast cancer when DNA adduct concentrations were doubled, with adjusted RR of 1.61 (95% CI 1.29-2.01). The increase in breast cancer risk was observed both for pre- and post-menopausal women. There was a significant interaction with tobacco smoking and body mass index, with higher effect of DNA adducts on breast cancer risk among smokers and women with normal weight. The results from our study support the hypothesis that factors leading to higher levels of aromatic DNA adducts in white blood cells may be involved in development of breast cancer.

Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study.

BACKGROUND: Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations. METHODS AND FINDINGS: Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88-0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77-0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85-0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs. CONCLUSIONS: These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.

Work, household, and leisure-time physical activity and risk of mortality in the EPIC-Spain cohort.

OBJECTIVE: Large-scale longitudinal data on the association of domain-specific physical activity (PA) and mortality is limited. Our objective was to evaluate the association of work, household (HPA), and leisure time PA (LTPA) with overall and cause-specific mortality in the EPIC-Spain study. METHODS: 38,379 participants (62.4% women), 30-65years old, and free of chronic disease at baseline were followed-up from recruitment (1992 - 1996) to December 31st, 2008 to ascertain vital status and cause of death. PA was evaluated at baseline and at a 3-year follow-up with a validated questionnaire (EPIC-PAQ) and combined variables were used to classify the participants by sub-domains of PA. Associations with overall, cancer, and cardiovascular mortality risks were assessed using competing risk Cox regression models adjusted by potential confounders. RESULTS: After 13.6years of mean follow-up, 1371 deaths were available for analyses. HPA was strongly associated to reduced overall (hazard ratio (HR) for Q4 vs. Q1=0.47 (0.34, 0.64)) and cause-specific mortalities in women and to lower cancer mortality in men (P for trend=0.004), irrespective of age, education, and lifestyle and morbidity variables. LTPA was associated with lower mortality in women (HR for Q4 vs. Q1=0.71 (0.52, 0.98)), but not men. No relationships were found between sedentariness at work and overall mortality. CONCLUSIONS: HPA was associated to lower mortality risk in men and women from the EPIC-Spain cohort, whereas LTPA also contributed to reduce risk of death in women. Considering the large proportion of total daily PA that HPA represents in some population groups, these results are of public health importance.

Resultados de dos encuestas dirigidas a inmigrantes y nativos del sureste español: salud, uso de servicios y necesidad de asistencia médica / Results of two surveys of immigrants and natives in Southeast Spain: health, use of services, and need for medical assistance

Objetivo. Comparar la salud, uso de servicios sanitarios y necesidad insatisfecha de atención médica (NIAM) entre inmigrantes y nativos del sureste español. Material y métodos. Estudio transversal de dos muestras representativas de población: inmigrante (n=1150) y nativa (n=1303; Encuesta Nacional de Salud). Se creó una única base de datos con ponderación específica para cada muestra y se estimaron razones de prevalencia (RP) mediante regresión multivariante. Resultados. Marroquíes, ecuatorianos y europeos del este (EE) declararon peor salud que los nativos (RPs [IC95%]: 2.45 [1.91-3.15]; 1.51 [1.28-1.79] y 1.44 [1.08-1.93], respectivamente). Los inmigrantes hicieron mayor uso de las urgencias (excepto EE) y consumieron menos fármacos. Los marroquíes mostraron la mayor diferencia en la frecuencia de NIAM (RP [IC95%]: 12.20 [5.25-28.37]), principalmente por razones laborales (46%). Conclusiones. La salud y el uso de servicios sanitarios difirieron significativamente entre inmigrantes y nativos. Destaca la NIAM alta en marroquíes por causa laboral.

Objective. To compare the self-perceived health, use of health services and unmet need for health care (UNHC) among immigrants and native populations of Southeast Spain. Materials and methods. Cross-sectional study of two representative samples of 1150 immigrants, and 1303 native participants from the National Health Survey. A single database was created with specific weights for each sample, and prevalence ratios (PR) were estimated by multivariate regression. Results. Moroccans, Ecuadorians and Eastern Europeans (EE) reported poorer health than the native population (PRs [CI95%]: 2.45 [1.91-3.15]; 1.51 [1.28-1.79] and 1.44 [1.08-1.93], respectively). Immigrants made greater use of emergencies that natives (except for EE) and had lower use of medication. Moroccan showed the greatest difference in the frequency of UNHC (PR [CI95%]:12.20 [5.25 - 28.37]), mainly because of working limitations (46%). Conclusions. The health status and use of health services among immigrants differ significantly from those of natives. Results highlight the higher frequency of UNHC among immigrants, especially high in Moroccans.

[Results of two surveys of immigrants and natives in Southeast Spain: health, use of services, and need for medical assistance]. / Resultados de dos encuestas dirigidas a inmigrantes y nativos del sureste español: salud, uso de servicios y necesidad de asistencia médica.

OBJECTIVE: To compare the self-perceived health, use of health services and unmet need for health care (UNHC) among immigrants and native populations of Southeast Spain. MATERIALS AND METHODS: Cross-sectional study of two representative samples of 1150 immigrants, and 1303 native participants from the National Health Survey. A single database was created with specific weights for each sample, and prevalence ratios (PR) were estimated by multivariate regression. RESULTS: Moroccans, Ecuadorians and Eastern Europeans (EE) reported poorer health than the native population (PRs [CI95%]: 2.45 [1.91-3.15]; 1.51 [1.28-1.79] and 1.44 [1.08-1.93], respectively). Immigrants made greater use of emergencies that natives (except for EE) and had lower use of medication. Moroccan showed the greatest difference in the frequency of UNHC (PR [CI95%]:12.20 [5.25 - 28.37]), mainly because of working limitations (46%). CONCLUSIONS: The health status and use of health services among immigrants differ significantly from those of natives. Results highlight the higher frequency of UNHC among immigrants, especially high in Moroccans.

Association between different obesity measures and the risk of stroke in the EPIC Spanish cohort.

INTRODUCTION: There is still a scientific debate on the exact role played by obesity on stroke risk. OBJECTIVE: The aim of the study was to analyze the association between obesity, measured by different indices such as body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and a new one called A Body Shape Index (ABSI) and the risk of total and ischemic stroke. SUBJECTS/METHODS: A total of 41,020 subjects (15,490 men and 25,530 women) aged 29-69 years participated in the study. All participants were recruited between 1992 and 1996 and followed up until 2008 to ascertain incident cerebrovascular disease events. Cox proportional hazards models were designed to estimate the relative risk and 95% CI between obesity and cerebrovascular disease incidence. RESULTS: After 13.8 years of follow-up, a total of 674 stroke cases (55.3% in men) were registered (531 ischemic, 79 hemorrhagic, 42 subarachnoid hemorrhage and 22 unspecified). WC fourth quartile (HR 1.95; 95% CI 1.20-3.19) and WHR fourth quartile (HR 1.58; 95% CI 1.12-2.25) were positively associated with total stroke only in men. BMI was not associated with stroke incidence. The new index, ABSI, was significantly associated with total stroke incidence only in men (HR 1.54; 95% CI 1.06-2.23). CONCLUSIONS: Data from the Spanish EPIC cohort study show a strong association of WC and WHR with the relative risk of suffering a stroke only in men, while no associations were found for BMI. It supports the suggestion of other authors of using more than one obesity index in the study of stroke risk prediction.

Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.

Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study.

BACKGROUND: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. METHODS AND FINDINGS: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10-4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10-3) and waist circumference (p for interaction  = 7.49×10-9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. CONCLUSIONS: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.

Aromatic adducts and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort.

In this case-cohort study, we examined the association between bulky DNA adducts and the risk of lung cancer within the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort with an average 7-year follow-up, including 98 cases of primary lung cancer and 296 subjects randomly selected from the cohort. Aromatic adducts were measured using (32)P-postlabeling in leukocyte DNA from blood samples collected at enrollment. The association between DNA adducts and the risk of lung cancer was estimated using a Cox proportional hazards model with a modified partial likelihood. There was an overall significant increased risk for developing lung cancer when DNA adduct concentrations were doubled, with relative risk (RR) adjusting for all relevant confounders of 1.36 with 95% confidence interval (CI) 1.18-157. There was a significant increased risk for developing lung cancer when DNA adduct concentrations were doubled for current smokers and among subjects exposed to PAH at work; there was also a slightly higher increase among males than females. However, no statistically significant differences were observed for the effect of adduct levels across smoking status, sex or occupational exposure to PAH. A meta-analysis combined four prospective studies, including this study, resulting in a significant association among current smokers, with an overall estimate of 34% increase in the risk of lung cancer when doubling the level of aromatic DNA adducts in leukocytes.

Active and passive cigarette smoking and breast cancer risk: results from the EPIC cohort.

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.

Non-invasive risk scores for prediction of type 2 diabetes (EPIC-InterAct): a validation of existing models.

BACKGROUND: The comparative performance of existing models for prediction of type 2 diabetes across populations has not been investigated. We validated existing non-laboratory-based models and assessed variability in predictive performance in European populations. METHODS: We selected non-invasive prediction models for incident diabetes developed in populations of European ancestry and validated them using data from the EPIC-InterAct case-cohort sample (27,779 individuals from eight European countries, of whom 12,403 had incident diabetes). We assessed model discrimination and calibration for the first 10 years of follow-up. The models were first adjusted to the country-specific diabetes incidence. We did the main analyses for each country and for subgroups defined by sex, age (<60 years vs ≥60 years), BMI (<25 kg/m(2)vs ≥25 kg/m(2)), and waist circumference (men <102 cm vs ≥102 cm; women <88 cm vs ≥88 cm). FINDINGS: We validated 12 prediction models. Discrimination was acceptable to good: C statistics ranged from 0·76 (95% CI 0·72-0·80) to 0·81 (0·77-0·84) overall, from 0·73 (0·70-0·76) to 0·79 (0·74-0·83) in men, and from 0·78 (0·74-0·82) to 0·81 (0·80-0·82) in women. We noted significant heterogeneity in discrimination (pheterogeneity<0·0001) in all but one model. Calibration was good for most models, and consistent across countries (pheterogeneity>0·05) except for three models. However, two models overestimated risk, DPoRT by 34% (95% CI 29-39%) and Cambridge by 40% (28-52%). Discrimination was always better in individuals younger than 60 years or with a low waist circumference than in those aged at least 60 years or with a large waist circumference. Patterns were inconsistent for BMI. All models overestimated risks for individuals with a BMI of <25 kg/m(2). Calibration patterns were inconsistent for age and waist-circumference subgroups. INTERPRETATION: Existing diabetes prediction models can be used to identify individuals at high risk of type 2 diabetes in the general population. However, the performance of each model varies with country, age, sex, and adiposity. FUNDING: The European Union.

Weight change later in life and colon and rectal cancer risk in participants in the EPIC-PANACEA study.

BACKGROUND: A moderate association exists between body mass index (BMI) and colorectal cancer. Less is known about the effect of weight change. OBJECTIVE: We investigated the relation between BMI and weight change and subsequent colon and rectal cancer risk. DESIGN: This was studied among 328,781 participants in the prospective European Prospective Investigation into Cancer-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating study (mean age: 50 y). Body weight was assessed at recruitment and on average 5 y later. Self-reported weight change (kg/y) was categorized in sex-specific quintiles, with quintiles 2 and 3 combined as the reference category (men: -0.6 to 0.3 kg/y; women: -0.4 to 0.4 kg/y). In the subsequent years, participants were followed for the occurrence of colon and rectal cancer (median period: 6.8 y). Multivariable Cox proportional hazards regression analyses were used to study the association. RESULTS: A total of 1261 incident colon cancer and 747 rectal cancer cases were identified. BMI at recruitment was statistically significantly associated with colon cancer risk in men (HR: 1.04; 95% CI: 1.02, 1.07). Moderate weight gain (quintile 4) in men increased risk further (HR: 1.32; 95% CI: 1.04, 1.68), but this relation did not show a clear trend. In women, BMI or weight gain was not related to subsequent risk of colon cancer. No statistically significant associations for weight loss and colon cancer or for BMI and weight changes and rectal cancer were found. CONCLUSIONS: BMI attained at adulthood was associated with colon cancer risk. Subsequent weight gain or loss was not related to colon or rectal cancer risk in men or women.

Smoking as a major risk factor for cervical cancer and pre-cancer: results from the EPIC cohort.

A total of 308,036 women were selected from the European Prospective Investigation into Cancer and Nutrition (EPIC) study to evaluate the association between tobacco smoking and the risk of cervical intraepithelial neoplasia of grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). At baseline, participants completed a questionnaire and provided blood samples. During a mean follow-up time of 9 years, 261 ICC cases and 804 CIN3/CIS cases were reported. In a nested case-control study, the baseline 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 (CT), and Human Herpes Virus 2 (HHV-2). Cervical samples were not available for HPV-DNA analysis in this study. Multivariate analyses were used to estimate associations between smoking and risk of CIN3/CIS and ICC in the cohort and the case-control studies. In the cohort analyses smoking status, duration and intensity showed a two-fold increased risk of CIN3/CIS and ICC, while time since quitting was associated with a two-fold reduced risk. In the nested case-control study, consistent associations were observed after adjustment for HPV, CT and HHV-2 serostatus, in both HPV seronegative and seropositive women. Results from this large prospective study confirm the role of tobacco smoking as an important risk factor for both CIN3/CIS and ICC, even after taking into account HPV exposure as determined by HPV serology. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation.

Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in European populations.

Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3.99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases. We used country-specific Prentice-weighted Cox regression models and random-effects meta-analysis methods to estimate HRs. Among the flavanol subclass, we observed significant inverse trends between intakes of all individual flavan-3-ol monomers and risk of T2D in multivariable models (all P-trend < 0.05). We also observed significant trends for the intakes of proanthocyanidin dimers (HR for the highest vs. the lowest quintile: 0.81; 95% CI: 0.71, 0.92; P-trend = 0.003) and trimers (HR: 0.91; 95% CI: 0.80, 1.04; P-trend = 0.07) but not for proanthocyanidins with a greater polymerization degree. Among the flavonol subclass, myricetin (HR: 0.77; 95% CI: 0.64, 0.93; P-trend = 0.001) was associated with a lower incidence of T2D. This large and heterogeneous European study showed inverse associations between all individual flavan-3-ol monomers, proanthocyanidins with a low polymerization degree, and the flavonol myricetin and incident T2D. These results suggest that individual flavonoids have different roles in the etiology of T2D.

The association between dietary flavonoid and lignan intakes and incident type 2 diabetes in European populations: the EPIC-InterAct study.

OBJECTIVE: To study the association between dietary flavonoid and lignan intakes, and the risk of development of type 2 diabetes among European populations. RESEARCH DESIGN AND METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct case-cohort study included 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 participants from among 340,234 participants with 3.99 million person-years of follow-up in eight European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the Phenol-Explorer, the U.K. Food Standards Agency, and the U.S. Department of Agriculture databases. Hazard ratios (HRs) from country-specific Prentice-weighted Cox regression models were pooled using random-effects meta-analysis. RESULTS: In multivariable models, a trend for an inverse association between total flavonoid intake and type 2 diabetes was observed (HR for the highest vs. the lowest quintile, 0.90 [95% CI 0.77-1.04]; P value trend = 0.040), but not with lignans (HR 0.88 [95% CI 0.72-1.07]; P value trend = 0.119). Among flavonoid subclasses, flavonols (HR 0.81 [95% CI 0.69-0.95]; P value trend = 0.020) and flavanols (HR 0.82 [95% CI 0.68-0.99]; P value trend = 0.012), including flavan-3-ol monomers (HR 0.73 [95% CI 0.57-0.93]; P value trend = 0.029), were associated with a significantly reduced hazard of diabetes. CONCLUSIONS: Prospective findings in this large European cohort demonstrate inverse associations between flavonoids, particularly flavanols and flavonols, and incident type 2 diabetes. This suggests a potential protective role of eating a diet rich in flavonoids, a dietary pattern based on plant-based foods, in the prevention of type 2 diabetes.

Age at menarche and type 2 diabetes risk: the EPIC-InterAct study.

OBJECTIVE: Younger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by adiposity. RESEARCH DESIGN AND METHODS: The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI. RESULTS: Mean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m2 lower adult BMI. Women in the earliest menarche quintile (8-11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio [HR], 1.70; 95% CI, 1.49-1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18-1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes. CONCLUSIONS: Women with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk.

Prevalence of obesity and associated cardiovascular risk: the DARIOS study.

BACKGROUND: To estimate the prevalence of overweight and obesity in the Spanish population as measured with body mass index (BMI), waist circumference (WC) and waist to height ratio (WHtR) and to determine the associated cardiovascular risk factors. METHODS: Pooled analysis with individual data from 11 studies conducted in the first decade of the 21st century. Participants aged 35-74 years were asked about the history of cardiovascular diseases, hypertension, diabetes and hypercholesterolemia. Height, weight, WC, blood pressure, glycaemia, total cholesterol, low-density and high-density lipoprotein cholesterol and coronary risk were measured. The prevalence of overweight (BMI 25-29.9 kg/m(2)), general obesity (BMI ≥ 30 kg/m(2)), suboptimal WC (≥ 80 cm and < 88 in women, ≥ 94 and < 102 in men), abdominal obesity (WC ≥88 cm ≥102 cm in women and men, respectively) and WHtR ≥0.5 was estimated, standardized for the European population. RESULTS: We included 28,743 individuals. The prevalence of overweight and suboptimal WC was 51% and 30% in men and 36% and 22% in women, respectively; general obesity was 28% in both sexes and abdominal obesity 36% in men and 55% in women. The prevalence of WHtR ≥0.5 was 89% and 77% in men and women, respectively. All cardiovascular risk factors were significantly associated with abnormal increased values of BMI, WC and WHtR. Hypertension showed the strongest association with overweight [OR = 1.99 (95% confidence interval 1.81-2.21) and OR = 2.10 (1.91-2.31)]; suboptimal WC [OR = 1.78 (1.60-1.97) and OR = 1.45 (1.26-1.66)], with general obesity [OR = 4.50 (4.02-5.04), and OR = 5.20 (4.70-5.75)] and with WHtR ≥0.5 [OR = 2.94 (2.52-3.43), and OR = 3.02 (2.66-3.42)] in men and women respectively, besides abdominal obesity in men only [OR = 3.51 (3.18-3.88)]. Diabetes showed the strongest association with abdominal obesity in women [OR = 3,86 (3,09-4,89). CONCLUSIONS: The prevalence of obesity in Spain was high. Overweight, suboptimal WC, general, abdominal obesity and WHtR ≥0.5 was significantly associated with diabetes, hypertension, hypercholesterolemia and coronary risk. The use of lower cut-off points for both BMI and particularly WC and could help to better identify the population at risk and therefore achieve more effective preventive measures.

Dietary flavonoid, lignan and antioxidant capacity and risk of hepatocellular carcinoma in the European prospective investigation into cancer and nutrition study.

Limited epidemiological evidence suggests a protective role for plant foods rich in flavonoids and antioxidants in hepatocellular cancer (HCC) etiology. Our aim was to prospectively investigate the association between dietary intake of flavonoids, lignans and nonenzymatic antioxidant capacity (NEAC) and HCC risk. Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 477,206 subjects (29.8% male) recruited from ten Western European countries, was analyzed. Flavonoid, lignan and NEAC intakes were calculated using a compilation of existing food composition databases linked to dietary information from validated dietary questionnaires. Dietary NEAC was based on ferric reducing antioxidant capacity (FRAP) and total radical-trapping antioxidant parameter (TRAP). Hepatitis B/C status was measured in a nested case-control subset. During a mean follow-up of 11-years, 191 incident HCC cases (66.5% men) were identified. Using Cox regression, multivariable adjusted models showed a borderline nonsignificant association of HCC with total flavonoid intake (highest versus lowest tertile, HR = 0.65, 95% CI: 0.40-1.04; p(trend) = 0.065), but not with lignans. Among flavonoid subclasses, flavanols were inversely associated with HCC risk (HR = 0.62, 95% CI: 0.39-0.99; p(trend) = 0.06). Dietary NEAC was inversely associated with HCC (FRAP: HR 0.50, 95% CI: 0.31-0.81; p(trend) = 0.001; TRAP: HR 0.49, 95% CI: 0.31-0.79; p(trend) = 0.002), but statistical significance was lost after exclusion of the first 2 years of follow-up. This study suggests that higher intake of dietary flavanols and antioxidants may be associated with a reduced HCC risk.

Risk of type 2 diabetes according to traditional and emerging anthropometric indices in Spain, a Mediterranean country with high prevalence of obesity: results from a large-scale prospective cohort study.

BACKGROUND: Obesity is a major risk factor for type 2 diabetes mellitus (T2DM). A proper anthropometric characterisation of T2DM risk is essential for disease prevention and clinical risk assessement. METHODS: Longitudinal study in 37 733 participants (63% women) of the Spanish EPIC (European Prospective Investigation into Cancer and Nutrition) cohort without prevalent diabetes. Detailed questionnaire information was collected at baseline and anthropometric data gathered following standard procedures. A total of 2513 verified incident T2DM cases occurred after 12.1 years of mean follow-up. Multivariable Cox regression was used to calculate hazard ratios of T2DM by levels of anthropometric variables. RESULTS: Overall and central obesity were independently associated with T2DM risk. BMI showed the strongest association with T2DM in men whereas waist-related indices were stronger independent predictors in women. Waist-to-height ratio revealed the largest area under the ROC curve in men and women, with optimal cut-offs at 0.60 and 0.58, respectively. The most discriminative waist circumference (WC) cut-off values were 99.4 cm in men and 90.4 cm in women. Absolute risk of T2DM was higher in men than women for any combination of age, BMI and WC categories, and remained low in normal-waist women. The population risk of T2DM attributable to obesity was 17% in men and 31% in women. CONCLUSIONS: Diabetes risk was associated with higher overall and central obesity indices even at normal BMI and WC values. The measurement of waist circumference in the clinical setting is strongly recommended for the evaluation of future T2DM risk in women.