Gaussian Graphical Models Identify Networks of Dietary Intake in a German Adult Population.

BACKGROUND: Data-reduction methods such as principal component analysis are often used to derive dietary patterns. However, such methods do not assess how foods are consumed in relation to each other. Gaussian graphical models (GGMs) are a set of novel methods that can address this issue. OBJECTIVE: We sought to apply GGMs to derive sex-specific dietary intake networks representing consumption patterns in a German adult population. METHODS: Dietary intake data from 10,780 men and 16,340 women of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort were cross-sectionally analyzed to construct dietary intake networks. Food intake for each participant was estimated using a 148-item food-frequency questionnaire that captured the intake of 49 food groups. GGMs were applied to log-transformed intakes (grams per day) of 49 food groups to construct sex-specific food networks. Semiparametric Gaussian copula graphical models (SGCGMs) were used to confirm GGM results. RESULTS: In men, GGMs identified 1 major dietary network that consisted of intakes of red meat, processed meat, cooked vegetables, sauces, potatoes, cabbage, poultry, legumes, mushrooms, soup, and whole-grain and refined breads. For women, a similar network was identified with the addition of fried potatoes. Other identified networks consisted of dairy products and sweet food groups. SGCGMs yielded results comparable to those of GGMs. CONCLUSIONS: GGMs are a powerful exploratory method that can be used to construct dietary networks representing dietary intake patterns that reveal how foods are consumed in relation to each other. GGMs indicated an apparent major role of red meat intake in a consumption pattern in the studied population. In the future, identified networks might be transformed into pattern scores for investigating their associations with health outcomes.

Main nutrient patterns are associated with prospective weight change in adults from 10 European countries.

PURPOSE: Various food patterns have been associated with weight change in adults, but it is unknown which combinations of nutrients may account for such observations. We investigated associations between main nutrient patterns and prospective weight change in adults. METHODS: This study includes 235,880 participants, 25-70 years old, recruited between 1992 and 2000 in 10 European countries. Intakes of 23 nutrients were estimated from country-specific validated dietary questionnaires using the harmonized EPIC Nutrient DataBase. Four nutrient patterns, explaining 67 % of the total variance of nutrient intakes, were previously identified from principal component analysis. Body weight was measured at recruitment and self-reported 5 years later. The relationship between nutrient patterns and annual weight change was examined separately for men and women using linear mixed models with random effect according to center controlling for confounders. RESULTS: Mean weight gain was 460 g/year (SD 950) and 420 g/year (SD 940) for men and women, respectively. The annual differences in weight gain per one SD increase in the pattern scores were as follows: principal component (PC) 1, characterized by nutrients from plant food sources, was inversely associated with weight gain in men (-22 g/year; 95 % CI -33 to -10) and women (-18 g/year; 95 % CI -26 to -11). In contrast, PC4, characterized by protein, vitamin B2, phosphorus, and calcium, was associated with a weight gain of +41 g/year (95 % CI +2 to +80) and +88 g/year (95 % CI +36 to +140) in men and women, respectively. Associations with PC2, a pattern driven by many micro-nutrients, and with PC3, a pattern driven by vitamin D, were less consistent and/or non-significant. CONCLUSIONS: We identified two main nutrient patterns that are associated with moderate but significant long-term differences in weight gain in adults.

Untargeted metabolic profiling identifies altered serum metabolites of type 2 diabetes mellitus in a prospective, nested case control study.

BACKGROUND: Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal the comprehensive metabolic alterations preceding the onset of T2D. METHODS: We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable-adjusted conditional logistic regression to assess the association of these metabolites with T2D. RESULTS: Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5'-monophosphate with incident T2D. CONCLUSIONS: This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites.

Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study.

UNLABELLED: The association between vitamin D status and hepatocellular carcinoma (HCC) has not been well investigated, despite experimental evidence supporting an important role of vitamin D in liver pathophysiology. Our objective was to investigate the association between prediagnostic circulating 25-hydroxyvitamin D [25(OH)D] serum levels and the risk of HCC in a prospective, nested case-control study among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Each case (n = 138) diagnosed between 1992 and 2010 was matched to one control by age, sex, study center, date and time of blood collection, and fasting status. Serum baseline levels of 25(OH)D were measured by liquid chromatography/tandem mass spectrometry. Multivariable incident rate ratios (IRRs) of HCC associated with continuous (per 10 nmol/L) or categorical levels (tertiles or a priori-defined categories) of prediagnostic 25(OH)D were calculated using conditional logistic regression. Higher 25(OH)D levels were associated with a 49% reduction in the risk of HCC (highest versus lowest tertile: multivariable IRR = 0.51, 95% confidence interval [CI], 0.26 to 0.99; Ptrend = 0.04; per 10 nmol/L increase: IRR = 0.80, 95% CI, 0.68-0.94). The finding did not vary substantially by time from enrolment to diagnosis, and did not change after adjustment for biomarkers of preexisting liver damage, nor chronic infection with hepatitis B or C viruses. The findings were not modified by body size or smoking status. CONCLUSION: In this prospective study on western European populations, serum levels of 25(OH)D were inversely associated with the risk of HCC. Given the rising incidence of this cancer in low-risk developed countries and the strong public health interest surrounding the potentially cancer-protective roles of vitamin D, additional studies in different populations are required.

Plasma fibroblast growth factor 23 and risk of cardiovascular disease: results from the EPIC-Germany case-cohort study.

Increased fibroblast growth factor 23 (FGF23) concentrations have emerged as a novel risk factor for heart failure and stroke but not for myocardial infarction (MI). Yet, most studies on MI were conducted in coronary artery disease (CAD) patients and the elderly. Evidence is unclear in subjects without CAD and for stroke subtypes. We investigated the relationships between FGF23 and overall major cardiovascular endpoints, incident MI, ischemic (IS) and haemorrhagic stroke (HS) in middle-aged adults without pre-existing cardiovascular disease. We used a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition-Germany, including a randomly drawn subcohort (n = 1,978), incident MI (n = 463) and stroke cases (n = 359 IS; n = 88 HS) identified during a mean follow-up of 8.2 years. Compared with participants with FGF23 levels in the lowest quartile, those in the highest quartile had a 36% increased risk for cardiovascular events [hazard ratio: 1.36, 95% confidence interval (CI): 1.02-1.82] after adjustment for established cardiovascular risk factors, patahyroid hormone and 25-hydroxyvitamin D3 levels, dietary calcium and phosphorus intake, and kidney function. However, sub-analyses revealed significant relationships with risk of MI and HS, but not IS. Compared with the lowest quartile, individuals in the top two FGF23 quartiles had a 1.62 (95% CI 1.07-2.45) fold increased risk for MI and a 2.61 (95% CI 1.23-5.52) fold increase for HS. Increased FGF23 emerged as a risk factor for both MI and HS. Further studies are warranted to confirm these results and to identify underlying mechanisms.

Adiponectin and risk of stroke: prospective study and meta-analysis.

BACKGROUND AND PURPOSE: The favorable cardiovascular effects attributed to adiponectin may lower risk of stroke. We investigated this in a prospective study and meta-analysis. METHODS: A case-cohort study nested within the Potsdam cohort of the European Prospective Investigation into Cancer was performed, with 170 incident cases of ischemic stroke and a randomly selected subcohort of 2155 participants without major cardiovascular disease at baseline. A random-effects dose-response meta-analysis was performed on prospective studies reporting on adiponectin and incident stroke in healthy populations up to April 2013, identified through MEDLINE and EMBASE. RESULTS: In European Prospective Investigation into Cancer-Potsdam, after adjustment for cardiovascular risk factors, the hazard ratio of ischemic stroke per 5-µg/mL higher total-adiponectin was 1.10 (95% confidence interval, 0.89-1.37). Participants with higher total-adiponectin had higher high-density lipoprotein-cholesterol and lower high-sensitivity C-reactive protein and triglyceride levels, and had less often diabetes mellitus. Additional adjustment for these putative mediators yielded a hazard ratio of 1.31 (95% confidence interval, 1.04-1.64). Nine studies (19,259 participants, 2960 cases), including European Prospective Investigation into Cancer-Potsdam, were meta-analyzed. Pooling relative risks adjusted for cardiovascular risk factors not including putative mediators indicated moderate between-study heterogeneity (I2=52.2%). This was explained by the smallest study, and the pooled relative risk (95% confidence interval) before and after its exclusion was 1.03 (0.98-1.08) and 0.99 (0.96-1.01) per 5 µg/mL, respectively. The pooled relative risk (95% confidence interval) additionally adjusted for potential mediators was 1.08 (1.01-1.15) and 1.05 (1.00-1.11) before and after excluding the same study, respectively. CONCLUSIONS: Adiponectin is not associated with risk of stroke. If anything, adiponectin relates directly to stroke risk after controlling for risk factors that favorably correlate with adiponectin.

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.

Dietary, lifestyle, and genetic determinants of vitamin D status: a cross-sectional analysis from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany study.

PURPOSE: Considerable variation in 25-hydroxyvitamin D (25(OH)D) in populations worldwide that seems to be independent of latitude has been reported. Therefore, we aimed to assess vitamin D status of a mid-aged German general population and to identify its dietary, lifestyle, anthropometric, and genetic determinants. METHODS: 25(OH)D concentrations were measured by LC-MS/MS in plasma samples of a random subcohort of the German arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) comprising 2,100 subjects aged 35-65 years. Associations between potential predictors and 25(OH)D were assessed by linear regression models. RESULTS: 32.8% of the variance in 25(OH)D was explained by a multivariable regression model, with season being the by far strongest predictor (semi-partial R²: 14.6%). Sex, waist circumference, leisure time physical activity, smoking, polymorphisms in the GC, CYP2R1, and DHCR7 genes, supplement use, exogenous hormone use, alcohol consumption, egg consumption, and fish consumption were significantly associated with 25(OH)D concentrations as well. However, none of these factors explained >2.3% of the variance in 25(OH)D. CONCLUSION: Even with a comprehensive set of genetic, anthropometric, dietary, and lifestyle correlates, not more than 32.8% of the variation in 25(OH)D could be explained in the EPIC-Germany study, implying that vitamin D prediction scores may not provide an appropriate proxy for measured 25(OH)D. Food intake was only a weak predictor of 25(OH)D concentrations, while a strong seasonal fluctuation in 25(OH)D was shown.

Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: a nested case-control study.

Experimental evidence suggests that vitamin D might play a role in the development of breast cancer. Although the results of case-control studies indicate that circulating 25-hydroxyvitamin D [25(OH)D] is inversely associated with the risk of breast cancer, the results of prospective studies are inconsistent. A case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) was carried out comprising 1,391 incident breast cancer cases and 1,391 controls. Multivariable conditional logistic regression models did not reveal a significant overall association between season-standardized 25(OH)D levels and the risk of breast cancer (ORQ4-Q1 [95% CI]: 1.07 [0.85-1.36], ptrend = 0.67). Moreover, 25(OH)D levels were not related to the risks of estrogen receptor positive tumors (ORQ4-Q1 [95% CI]: 0.97 [0.67-1.38], ptrend = 0.90) and estrogen receptor negative tumors (ORQ4-Q1 [95% CI]: 0.97 [0.66-1.42], ptrend = 0.98). In hormone replacement therapy (HRT) users, 25(OH)D was significantly inversely associated with incident breast cancer (ORlog2 [95% CI]: 0.62 [0.42-0.90], p = 0.01), whereas no significant association was found in HRT nonusers (ORlog2 [95% CI]: 1.14 [0.80-1.62], p = 0.48). Further, a nonsignificant inverse association was found in women with body mass indices (BMI) < 25 kg/m(2) (ORlog2 [95% CI]: 0.83 [0.67-1.03], p = 0.09), as opposed to a borderline significant positive association in women with BMI ≥ 25 kg/m(2) (ORlog2 [95% CI]: 1.30 [1.0-1.69], p = 0.05). Overall, prediagnostic levels of circulating 25(OH)D were not related to the risk of breast cancer in the EPIC study. This result is in line with findings in the majority of prospective studies and does not support a role of vitamin D in the development of breast cancer.

Microsomal triglyceride transfer protein -164 T > C gene polymorphism and risk of cardiovascular disease: results from the EPIC-Potsdam case-cohort study.

BACKGROUND: The microsomal triglyceride transfer protein (MTTP) is encoded by the MTTP gene that is regulated by cholesterol in humans. Previous studies investigating the effect of MTTP on ischemic heart disease have produced inconsistent results. Therefore, we have tested the hypothesis that the rare allele of the -164T > C polymorphism in MTTP alters the risk of cardiovascular disease (CVD), depending on the cholesterol levels. METHODS: The -164T > C polymorphism was genotyped in a case-cohort study (193 incident myocardial infarction (MI) and 131 incident ischemic stroke (IS) cases and 1 978 non-cases) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, comprising 27 548 middle-aged subjects. The Heinz Nixdorf Recall study (30 CVD cases and 1 188 controls) was used to replicate our findings. RESULTS: Genotype frequencies were not different between CVD and CVD free subjects (P = 0.79). We observed an interaction between the -164T > C polymorphism and total cholesterol levels in relation to future CVD. Corresponding stratified analyses showed a significant increased risk of CVD (HR(additve) = 1.38, 95% CI: 1.07 to 1.78) for individuals with cholesterol levels <200 mg/dL in the EPIC-Potsdam study. HR(additive) was 1.06, 95% CI: 0.33 to 3.40 for individuals in the Heinz Nixdorf Recall study. A borderline significant decrease in CVD risk was observed in subjects with cholesterol levels ≥ 200 mg/dL (HR(additve) = 0.77, 95% CI: 0.58 to 1.03) in the EPIC-Potsdam study. A similar trend was observed in the independent cohort (HR(additve) = 0.60, 95% CI: 0.29 to 1.25). CONCLUSIONS: Our study suggests an interaction between MTTP -164T > C functional polymorphism with total cholesterol levels. Thereby risk allele carriers with low cholesterol levels may be predisposed to an increased risk of developing CVD, which seems to be abolished among risk allele carriers with high cholesterol levels.

Dietary intake of vitamin D and calcium and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Studies assessing the effects of vitamin D or calcium intake on breast cancer risk have been inconclusive. Furthermore, few studies have evaluated them jointly. This study is the largest so far examining the association of dietary vitamin D and calcium intake with breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. During a mean follow-up of 8.8 yr, 7760 incident invasive breast cancer cases were identified among 319,985 women. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pre- and postmenopausal breast cancer risk. Comparing the highest with the lowest quintile of vitamin D intake, HR and 95% CI were 1.07 (0.87-1.32) and 1.02 (0.90-1.16) for pre- and postmenopausal women, respectively. The corresponding HR and 95% CIs for calcium intake were 0.98 (0.80-1.19) and 0.90 (0.79-1.02), respectively. For calcium intake in postmenopausal women, the test for trend was borderline statistically significant (P(trend) = 0.05). There was no significant interaction between vitamin D and calcium intake and cancer risk (P(interaction) = 0.57 and 0.22 in pre- and postmenopausal women, respectively). In this large prospective cohort, we found no evidence for an association between dietary vitamin D or calcium intake and breast cancer risk.

Fish consumption and the risk of myocardial infarction and stroke in the German arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Germany).

Recent meta-analyses have confirmed that fish consumption is related to decreased risks of ischaemic stroke and fatal CHD, while there seem to be no clear associations between fish consumption and the risks of haemorrhagic stroke and non-fatal CHD. As no studies in German populations have been reported to date, we assessed whether fish consumption as recorded by FFQ between 1994 and 1998 was related to incident myocardial infarction (MI) and stroke within the German arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards regression analyses were conducted based on the data of 48 315 participants aged 35­65 years at baseline. The median fish intake was 16·4 g/d (25th­75th percentile 8·2­28·8 g/d). During a mean follow-up of 8·1 years, 605 incident MI and 525 incident strokes have been documented. After multiple adjustment, fish consumption was not related to incident MI (hazard ratio (HR) 0·84, 95 % CI 0·66, 1·08, P trend= 0·21) or stroke (HR 0·96, 95 % CI 0·73, 1·26, P trend= 0·67). Separate analyses for fatal MI, ischaemic stroke and haemorrhagic stroke did not show significant associations, either. With regard to non-fatal MI, there was a non-significant trend for an inverse association (HR 0·78, 95 % CI 0·59, 1·03, P trend= 0·07). Overall, fish consumption was not related to the risks of MI and stroke in the EPIC-Germany study.

Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident type 2 diabetes: a prospective case-cohort study.

It is unclear whether vitamin D lowers risk of type 2 diabetes (T2D). In an observational study, we assessed the prospective association between plasma 25-hydroxyvitamin D (25(OH)D) and incident T2D, and evaluated whether it holds up for genetically determined elevated 25(OH)D. We used a case-cohort study nested within the German arm of the European Prospective Investigation into Cancer. From a total cohort of 53,088 participants with a mean follow-up of 6.6 years, we identified a random subcohort of 2,121 participants (57% women) and 1,572 incident cases of T2D. 25(OH)D was measured in baseline plasma samples retrieved from frozen storage. Mean plasma 25(OH)D in the subcohort was 47.1 (5th-95th percentile 19.6-80.7) nmol/L. After controlling for age, sex, center, season of blood draw, education, and lifestyle, the hazard of T2D decreased across increasing plasma concentrations of 25(OH)D (P linear trend<0.0001). The association became non-linear after adjustment for BMI and waist circumference (P non-linearity<0.0001), with the inverse association being restricted to participants with 25(OH)D concentrations below ~45 nmol/L (hazard ratio per 5 nmol/L higher 25(OH)D 0.91, 95% CI 0.84-0.98). A score predicting genetically determined plasma 25(OH)D by weighting four independent single-nucleotide polymorphisms by their effect on 25(OH)D, explained 3.7% of the variance in 25(OH)D. The hazard ratio (95% CI) per 5 nmol/L higher genetically predicted 25(OH)D was 0.98 (0.89-1.08) in the entire study sample and 1.06 (0.93-1.21) in the sub-sample with 25(OH)D<45 nmol/L. This latter finding casts doubt on a strong causal association of 25(OH)D with T2D, but further research in large-scale consortia is needed.

Mediterranean diet and colorectal cancer risk: results from a European cohort.

The authors investigated the association of adherence to Mediterranean diet with colorectal cancer (CRC) risk in the European Prospective Investigation into Cancer and nutrition study. Adherence to Mediterranean diet was expressed through two 10-unit scales, the Modified Mediterranean diet score (MMDS) and the Centre-Specific MMDS (CSMMDS). Both scales share the same dietary components but differ in the cut-off values that were used for these components in the construction of the scales. Adjusted hazard ratios (HR) for the associations of these scales with CRC incidence were estimated. After 5,296,617 person-years of follow-up, 4,355 incident CRC cases were identified. A decreased risk of CRC, of 8 and 11 % was estimated when comparing the highest (scores 6-9) with the lowest (scores 0-3) adherence to CSMMDS and MMDS respectively. For MMDS the HR was 0.89 (95 % confidence interval (CI): 0.80, 0.99). A 2-unit increment in either Mediterranean scale was associated with a borderline statistically significant 3 to 4 % reduction in CRC risk (HR for MMDS: 0.96; 95 % CI: 0.92, 1.00). These associations were somewhat more evident, among women, were mainly manifested for colon cancer risk and their magnitude was not altered when alcohol was excluded from MMDS. These findings suggest that following a Mediterranean diet may have a modest beneficial effect on CRC risk.

Fish consumption does not prevent increase in waist circumference in European women and men.

Fish consumption is the major dietary source of EPA and DHA, which according to rodent experiments may reduce body fat mass and prevent obesity. However, human studies have suggested that fish consumption has no appreciable association with body-weight gain. We investigated the associations between fish consumption and subsequent change in waist circumference. Sex, age and waist circumference at enrolment were considered as potential effect modifiers. Women and men (n 89 432) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) were followed for a median of 5·5 years. Mixed-effect linear regression was used to investigate the associations between fish consumption and subsequent change in waist circumference. Among all participants, the average annual change in waist circumference was - 0·01 cm/10 g higher total fish consumption per d (95 % CI - 0·01, 0·00) and - 0·01 cm/10 g higher fatty fish consumption per d (95 % CI - 0·02, - 0·01), after adjustment for potential confounders. Lean fish consumption was not associated with change in waist circumference. Adjustment for potential over- or underestimation of fish consumption measurements did not systematically change the observed associations, but the 95 % CI became slightly wider. The results in subgroups from analyses stratified by sex, age or waist circumference at enrolment were not systematically different. In conclusion, the present study suggests that fish consumption does not prevent increase in waist circumference.

Risk assessment tools for identifying individuals at risk of developing type 2 diabetes.

Trials have demonstrated the preventability of type 2 diabetes through lifestyle modifications or drugs in people with impaired glucose tolerance. However, alternative ways of identifying people at risk of developing diabetes are required. Multivariate risk scores have been developed for this purpose. This article examines the evidence for performance of diabetes risk scores in adults by 1) systematically reviewing the literature on available scores and 2) their validation in external populations; and 3) exploring methodological issues surrounding the development, validation, and comparison of risk scores. Risk scores show overall good discriminatory ability in populations for whom they were developed. However, discriminatory performance is more heterogeneous and generally weaker in external populations, which suggests that risk scores may need to be validated within the population in which they are intended to be used. Whether risk scores enable accurate estimation of absolute risk remains unknown; thus, care is needed when using scores to communicate absolute diabetes risk to individuals. Several risk scores predict diabetes risk based on routine noninvasive measures or on data from questionnaires. Biochemical measures, in particular fasting plasma glucose, can improve prediction of such models. On the other hand, usefulness of genetic profiling currently appears limited.

Plasma gamma-glutamyltransferase, cysteinyl-glycine, and oxidized low-density lipoprotein: a pathway associated with myocardial infarction risk?

OBJECTIVE: To investigate the interrelation between plasma γ-glutamyltransferase (GGT) activity, cysteinyl-glycine (Cys-Gly) (ie, a thiol originating from GGT-mediated cleavage of glutathione), and oxidized low-density lipoprotein (oxLDL) with regard to myocardial infarction (MI) risk in a prospective study. METHODS AND RESULTS: Incident cases of MI were identified among European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam participants without prior MI during 6.0 years of follow-up. Baseline levels of Cys-Gly and oxLDL and GGT activity in plasma were measured in a case-cohort study comprising 837 subjects without incident MI and 116 subjects with incident MI. The relation of GGT, Cys-Gly and oxLDL to MI risk was assessed using Cox proportional hazards regression analysis. After adjustment for established risk factors, hazard ratios associated with a 1-SD unit increase in the log-transformed biomarker were 1.63 (95% CI, 1.30 to 2.05) for GGT, 1.36 (95% CI, 1.07 to 1.72) for Cys-Gly, and 1.37 (95% CI, 1.00 to 1.86) for oxLDL. Cys-Gly and oxLDL accounted for 2.3% of the relation between GGT and MI risk. CONCLUSIONS: The positive association between GGT activity and MI risk appears to be independent of circulating Cys-Gly and oxLDL levels. With Cys-Gly, we found a potential new predictor of MI risk whose impact needs to be further elucidated.

Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults.

AIMS: To investigate the association of chocolate consumption with measured blood pressure (BP) and the incidence of cardiovascular disease (CVD). METHODS AND RESULTS: Dietary intake, including chocolate, and BP were assessed at baseline (1994-98) in 19 357 participants (aged 35-65 years) free of myocardial infarction (MI) and stroke and not using antihypertensive medication of the Potsdam arm of the European Prospective Investigation into Cancer and Nutrition. Incident cases of MI (n = 166) and stroke (n = 136) were identified after a mean follow-up of approximately 8 years. Mean systolic BP was 1.0 mmHg [95% confidence interval (CI) -1.6 to -0.4 mmHg] and mean diastolic BP 0.9 mmHg (95% CI -1.3 to -0.5 mmHg) lower in the top quartile compared with the bottom quartile of chocolate consumption. The relative risk of the combined outcome of MI and stroke for top vs. bottom quartiles was 0.61 (95% CI 0.44-0.87; P linear trend = 0.014). Baseline BP explained 12% of this lower risk (95% CI 3-36%). The inverse association was stronger for stroke than for MI. CONCLUSION: Chocolate consumption appears to lower CVD risk, in part through reducing BP. The inverse association may be stronger for stroke than for MI. Further research is needed, in particular randomized trials.

Association between serum gamma-glutamyltransferase and cardiovascular mortality varies by age: the Minnesota Heart Survey.

BACKGROUND: Although serum gamma-glutamyltransferase (GGT) predicted cardiovascular diseases (CVD) in prospective studies and may be useful in risk assessment, prediction in older adults was weaker in several studies. METHODS: We performed a nested case-control study with 5-12-year follow-up in 137 CVD deaths and 249 controls (frequency-matched on age, sex, and examination year, age range 26-85 years). RESULTS: An age interaction of serum GGT and CVD mortality (P value for interaction=0.02) was observed. After adjusting for known CVD risk factors, compared with the lowest tertile, odds ratios (95% confidence intervals) in participants less than 70 years (half the participants) were: middle tertile: 2.17 (0.68-6.97), top tertile up to GGT less than 50 U/l: 3.54 (1.07-11.7), and GGT >/=50 U/l: 4.69 (1.16-18.9). In participants aged more than or equal to 70 years, GGT was not related to CVD. Well-known demographic and health behavior associations with serum GGT were observed only in controls among participants aged less than 70 years. CONCLUSION: Our findings suggest that serum GGT within its normal range can predict CVD mortality in those aged less than 70 years, but may have limited usefulness for risk assessment in older adults.

Both alpha- and beta-carotene, but not tocopherols and vitamin C, are inversely related to 15-year cardiovascular mortality in Dutch elderly men.

The role of beta-carotene, alpha-tocopherol, and vitamin C in the prevention of cardiovascular diseases (CVD) is controversial. Prospective studies on gamma-tocopherol and carotenoids other than beta-carotene are sparse. We assessed relations between the intake of different carotenoids, alpha- and gamma-tocopherol, and vitamin C with 15-y CVD mortality in elderly men who participated in the Zutphen Elderly Study. Information on diet and potential confounding factors was collected in 1985, 1990, and 1995. In 1985, 559 men (mean age approximately 72 y) free of chronic diseases were included in the current analysis. After 15 y of follow-up, comprising 5744 person-years, 197 men had died from CVD. After adjustment for age, smoking, and other potential lifestyle and dietary confounders, relative risks (RR) (95% CI) of CVD death for a 1-SD increase in intake were 0.81 (0.66-0.99) for alpha-carotene and 0.80 (0.66-0.97) for beta-carotene. Carrots were the primary source of alpha- and beta-carotene and their consumption was related to a lower risk of death from CVD (adjusted RR, 0.83; 95% CI = 0.68-1.00). Intakes of carotenoids other than alpha- and beta-carotene were not associated with CVD mortality, nor were vitamin C and alpha- and gamma tocopherol. In conclusion, dietary intakes of alpha-carotene and beta-carotene are inversely associated with CVD mortality in elderly men. This study does not indicate an important role for other carotenoids, tocopherols, or vitamin C in lowering the risk of CVD death.