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OBJECTIVE Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value RESULTS Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: −0.009 mmol/l glucose [−0.013 to −0.005], P < 0.0001 and −0.011 pmol/l [ln] insulin [−0.015 to −0.007], P = 0.0003). No interactions met our multiple testing–adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. CONCLUSIONS Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

We studied the associations of three renin-angiotensin system polymorphisms, angiotensin-converting enzyme (ACE) I/D, angiotensinogen 235 M/T, and angiotensin II receptor type I 573 C/T, with arterial stiffness. The study was embedded in the Rotterdam Study, a population-based study older adults. The association of the polymorphisms with pulse wave velocity, the carotid distensibility, and pulse pressure was investigated in 3706 subjects. We found no association of the ACE I/D polymorphism with pulse wave velocity, but the D-allele was associated with a lower distensibility coefficient (p = 0.05) and higher pulse pressure (p = 0.01). For the angiotensinogen 235 M/T polymorphism, no significant associations with either pulse wave velocity (p = 0.71), the distensibility coefficient (p = 0.16) or pulse pressure (p = 0.34) were found. Also, we found no significant associations of pulse wave velocity (PWV) (p = 0.32), the distensibility coefficient (p = 0.08), and pulse pressure (p = 0.09) with the angiotensin II receptor type 1 573 C/T polymorphism. No epistatic effects were observed between the three renin-angiotensin system (RAS) genes with arterial stiffness. Our findings suggest that genetic variation in the renin-angiotensin system may play a role in determining carotid distensibility and pulse pressure.

Many prospective studies have reported associations between circulating C-reactive protein (CRP) levels and risk of coronary heart disease (CHD), but causality remains uncertain. Studies of CHD are being conducted that involve measurement of common polymorphisms of the CRP gene known to be associated with circulating concentrations, thereby utilising these variants as proxies for circulating CRP levels. By analysing data from several studies examining the association between relevant CRP polymorphisms and CHD risk, the present collaboration will undertake a Mendelian randomisation analysis to help assess the likelihood of any causal relevance of CRP levels to CHD risk. A central database is being established containing individual data on CRP polymorphisms, circulating CRP levels, and major coronary outcomes as well as age, sex and other relevant characteristics. Associations between CRP polymorphisms or haplotypes and CHD will be evaluated under different circumstances. This collaboration comprises, at present, about 37,000 CHD outcomes and about 120,000 controls, which should yield suitably precise findings to help judge causality. This work should advance understanding of the relevance of low-grade inflammation to CHD and indicate whether or not CRP itself is involved in long-term pathogenesis.

This study examined cross-sectionally the association of dietary beta-carotene, vitamin C, and vitamin E with peripheral arterial disease in Rotterdam, the Netherlands (1990--1993). The 4,367 subjects from the Rotterdam Study were aged 55--94 years and had no previous cardiovascular disease at baseline. Diet was assessed with a food frequency questionnaire. Peripheral arterial disease was defined as an ankle-arm systolic blood pressure index (AAI) of < or = 0.9 and was present in 204 men and 370 women. In multivariate-adjusted logistic regression analyses, vitamin C intake was significantly inversely associated with peripheral arterial disease in women (highest vs. lowest quartile: relative risk = 0.64, 95% confidence interval (CI): 0.48, 0.89; p(trend) = 0.006), and a 100-mg increase in intake was associated with a 0.013 AAI increase (95% CI: 0.001, 0.025). In men, vitamin E intake was inversely associated with peripheral arterial disease (relative risk = 0.67, 95% CI: 0.44, 1.03; p(trend) = 0.067); a 10-mg increase in intake was associated with a 0.015 AAI increase (95% CI: 0.001, 0.031). Whether these differences in antioxidant intake and the risk of a low AAI and of peripheral arterial disease between sexes are attributable to a different food pattern for men compared with women remains to be elucidated.

The net reclassification improvement (NRI) is an increasingly popular measure for evaluating improvements in risk predictions. This article details a review of 67 publications in high-impact general clinical journals that considered the NRI. Incomplete reporting of NRI methods, incorrect calculation, and common misinterpretations were found. To aid improved applications of the NRI, the article elaborates on several aspects of the computation and interpretation in various settings. Limitations and controversies are discussed, including the effect of miscalibration of prediction models, the use of the continuous NRI and "clinical NRI," and the relation with decision analytic measures. A systematic approach toward presenting NRI analysis is proposed: Detail and motivate the methods used for computation of the NRI, use clinically meaningful risk cutoffs for the category-based NRI, report both NRI components, address issues of calibration, and do not interpret the overall NRI as a percentage of the study population reclassified. Promising NRI findings need to be followed with decision analytic or formal cost-effectiveness evaluations.

PURPOSE: There is increasing evidence that epicardial fat (i.e., adipose tissue contained within the pericardium) plays an important role in the development of cardiovascular disease. Obtaining the epicardial fat volume from routinely performed non-enhanced cardiac CT scans is therefore of clinical interest. The purpose of this work is to investigate the feasibility of automatic pericardium segmentation and subsequent quantification of epicardial fat on non-enhanced cardiac CT scans. METHODS: Imaging data of 98 randomly selected subjects belonging to a larger cohort of subjects who underwent a cardiac CT scan at our medical center were retrieved. The data were acquired on two different scanners. Automatic multi-atlas based method for segmenting the pericardium and calculating the epicardial fat volume has been developed. The performance of the method was assessed by (1) comparing the automatically segmented pericardium to a manually annotated reference standard, (2) comparing the automatically obtained epicardial fat volumes to those obtained manually, and (3) comparing the accuracy of the automatic results to the inter-observer variability. RESULTS: Automatic segmentation of the pericardium was achieved with a Dice similarity index of 89.1 ± 2.6% with respect to Observer 1 and 89.2 ± 1.9% with respect to Observer 2. The correlation between the automatic method and the manual observers with respect to the epicardial fat volume computed as the Pearson's correlation coefficient (R) was 0.91 (P < 0.001) for both observers. The inter-observer study resulted in a Dice similarity index of 89.0 ± 2.4% for segmenting the pericardium and a Pearson's correlation coefficient of 0.92 (P

Background: Atrial fibrillation is the most common sustained arrhythmia in the elderly. Serum potassium is associated with ventricular arrhythmias and cardiac arrest. Little is known about the association of serum potassium with atrial fibrillation. The objective of this study was to investigate the association of serum potassium and the risk of atrial fibrillation in a population based setting. Methods: The study was performed within the prospective population-based Rotterdam Study. The study population consisted of 4059 participants without atrial fibrillation at baseline for whom baseline levels of serum potassium were measured. Atrial fibrillation was ascertained from centre visit ECG assessments as well as medical records. Results: During a mean follow up of 11.8 years (SD = 5.2 yr), 474 participants developed atrial fibrillation. Participants with hypokalemia (

Background: Whether newer risk markers for coronary heart disease (CHD) improve CHD risk prediction remains unclear. Objective: To assess whether newer risk markers for CHD risk prediction and stratification improve Framingham risk score (FRS) predictions. Design: Prospective population-based study. Setting: The Rotterdam Study, Rotterdam, the Netherlands. Participants: 5933 asymptomatic, community-dwelling participants (mean age, 69.1 years [SD, 8.5]). Measurements: Traditional CHD risk factors used in the FRS (age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and newer CHD risk factors (N-terminal fragment of prohormone B-type natriuretic peptide levels, von Willebrand factor antigen levels, fibrinogen levels, chronic kidney disease, leukocyte count, C-reactive protein levels, homocysteine levels, uric acid levels, coronary artery calcium [CAC] scores, c Results: Adding CAC scores to the FRS improved the accuracy of risk predictions (c-statistic increase, 0.05 [95% CI, 0.02 to 0.06]; net reclassification index, 19.3% overall [39.3% in those at intermediate risk, by FRS]). Levels of N-terminal fragment of prohormone B-type natriuretic peptide also improved risk predictions but to a lesser extent (c-statistic increase, 0.02 [CI, 0.01 to 0.04]; net reclassification index, 7.6% overall [33.0% in those at intermediate risk, by FRS]). Improvements in Limitation: The findings may not be generalizable to younger or nonwhite populations. Conclusion: Among 12 CHD risk markers, improvements in FRS predictions were most statistically and clinically significant with the addition of CAC scores. Further investigation is needed to assess whether risk refinements using CAC scores lead to a meaningful change in clinical outcome. Whether to use CAC score screening as a more routine test for risk prediction requires full consideration of the financial and clinical costs of performing versus not performing the test for both persons and heal

OBJECTIVES The purpose of this study was to determine the association of coronary artery calcification (CAC) with incident heart failure in the elderly and examine its independence of overt coronary heart disease (CHD). BACKGROUND Heart failure is often observed as a first manifestation of coronary atherosclerosis rather than a sequela of overt CHD. Although numerous studies have shown that CAC, an established measure of coronary atherosclerosis, is a strong predictor of CHD, the association between CAC and future heart failure has not been studied prospectively. METHODS In the Rotterdam Study, a population-based cohort, 1,897 asymptomatic participants (mean age, 69.9 years; 58% women) underwent CAC scoring and were followed for the occurrence of heart failure and CHD. RESULTS During a median follow-up of 6.8 years, there were 78 cases of heart failure and 76 cases of nonfatal CHD. After adjustment for cardiovascular risk factors, increasing CAC scores were associated with heart failure (p for trend = 0.001), with a hazard ratio of 4.1 (95% confidence interval [CI]: 1.7 to 10.1) for CAC scores >400 compared with CAC scores of 0 to 10. After censoring participants for incident nonfatal CHD, increasing extent of CAC remained associated with heart failure (p for CONCLUSIONS CAC has a clear association with the risk of heart failure, independent of overt CHD. Because heart failure is highly prevalent in the elderly, it might be worthwhile to include heart failure as an outcome in future risk assessment programs incorporating CAC. (J Am Coll Cardiol Img 2012;5:874-80) (C) 2012 by the American College of Cardiology Foundation

OBJECTIVE-To investigate whether intake of different types of meat is associated with circulating C-reactive protein (CRP) and risk of type 2 diabetes in a prospective cohort study. RESEARCH DESIGN AND METHODS-Our analysis included 4,366 Dutch participants who did not have diabetes at baseline. During a median follow-up period of 12.4 years, 456 diabetes cases were confirmed. Intake of red meat, processed meat, and poultry was derived from a food frequency questionnaire, and their association with serum high-sensitivity CRP was examined cross-sectionally using linear regression models. Their association with risk of type 2 diabetes was examined using multivariate Cox propor RESULTS-An increment of 50 g of processed meat was associated with increased CRP concentration (beta(processed meat) = 0.12; P = 0.01), whereas intake of red meat and poultry was not. When comparing the highest to the lowest category of meat intake with respect to diabetes incidence, the adjusted relative risks were as follows: for red meat (1.42 [95% CI 1.06-1.91]), for processed meat (1.87 [1.26-2.78]), and for poultry (0.95 [0.74-1.22]). Additional analysis showed that the associations were n CONCLUSIONS-Intake of processed meat is associated with higher risk of type 2 diabetes. It appears unlikely that CRP mediates this association.

Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P

Objective: To investigate whether dietary nutrients can reduce the genetic risk of early age-related macular degeneration (AMD) conferred by the genetic variants CFH Y402H and LOC387715 A69S in a nested case-control study. Methods: For 2167 individuals (>= 55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes. Results: Five hundred seventeen participants developed early AMD. Significant synergy indices supported the possibility of biological interaction between CFH Y402H and zinc, beta-carotene, lutein/zeaxanthin, and eicosapentaenoic/docosahexaenoic acid (EPA/DHA) and between LOC387715 A69S and zinc and EPA/DHA (all P < .05). Homozygotes of CFH Y402H with dietary intake of zinc in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of beta-carotene, lutein/zeaxanthin, and EPA/DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. Carriers of LOC387715 A69S with the highest intake of zinc and EPA/DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all P trends

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

Objectives The purpose of this study was to examine the effect of coronary artery calcium (CAC) on the classification of 10-year hard coronary heart disease (CHD) risk and to empirically derive cut-off values of the calcium score for a general population of elderly patients. Background Although CAC scoring has been found to improve CHD risk prediction, there are limited data on its impact in clinical practice. Methods The study comprised 2,028 asymptomatic participants (age 69.6 +/- 6.2 years) from the Rotterdam Study. During a median follow-up of 9.2 years, 135 hard coronary events occurred. Persons were classified into low (20%) 10-year coronary risk categories based on a Framingham refitted risk model. In a second step, the model was extended by CAC, and reclassification percentages were calculated. Cutoff values of CAC for persons in the intermediate-risk category were empirically derived based on 10-year hard CHD risk. Results Reclassification by means of CAC scoring was most substantial in persons initially classified as intermediate risk. In this group, 52% of men and women were reclassified, all into more accurate risk categories. CAC values above 615 or below 50 Agatston units were found appropriate to reclassify persons into high or low risk, respectively. Conclusions In a general population of elderly patients at intermediate CHD risk, CAC scoring is a powerful method to reclassify persons into more appropriate risk categories. Empirically derived CAC cutoff values at which persons at intermediate risk reclassified to either high or low risk were 615 and 50 Agatston units, respectively. (J Am Coll Cardiol 2010;56:1407-14) (C) 2010 by the American College of Cardiology Foundation

OBJECTIVE-To investigate the relationship between fasting glucose levels, insulin resistance, and cognitive impairment in old age. Diabetes is associated with cognitive impairment in older people. However, the link between elevated fasting glucose levels and insulin resistance in nondiabetic individuals, and the risk of cognitive impairment is unclear. RESEARCH DESIGN AND METHODS-We analyzed data from, in total, 8,447 participants in two independent prospective studies: the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), 5,019 participants, aged 69-84 years, and the Rotterdam Study, 3,428 participants, aged 61-97 years. Fasting glucose levels were assessed at baseline in both studies; fasting insulin levels were assessed in the Rotterdam Study only. Cognitive function was assessed in both studies at baseline and during follow-up. RESULTS-Subjects with diabetes had impaired cognitive function at baseline. In contrast, in people without a history of diabetes, there was no clear association between baseline fasting glucose levels and executive function and memory, nor was there a consistent relationship between elevated baseline fasting glucose levels and the rate of cognitive decline in either cohort. Insulin resistance (homeostasis model assessment index) was also unrelated to cognitive function and decline. CONCLUSIONS-Elevated fasting glucose levels and insulin resistance are not associated with worse cognitive function in older people without a history of diabetes. These data suggest either that there is a threshold for effects of dysglycemia on cognitive function or that factors other than hyperglycemia contribute to cognitive impairment in individuals with frank diabetes. Diabetes 59:1601-1607, 2010

OBJECTIVE-There is a complex relationship between IGF-I, IGF binding proteins, growth hormone, and insulin. The IGF-I kinase receptor activation assay (KIRA) is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of IGF-I bioactivity might broaden our understanding of the IGF-I system in subjects with the metabolic syndrome. The purpose of our study was to investigate whether IGF-I bioactivity was related to insulin sensitivity and the metabolic syndrome. RESEARCH DESIGN AND METHODS-We conducted a cross-sectional study embedded in a random sample (1,036 elderly subjects) of a prospective population-based cohort study. IGF-I bioactivity was determined by the IGF-I KIRA. Categories of glucose (in)tolerance were defined by the 2003 American Diabetes Association criteria. Insulin sensitivity was assessed by homeostasis model assessment. The Adult Treatment Panel III definition of the metabolic syndrome was used. RESULTS-In subjects with normal fasting glucose and impaired fasting glucose, IGF-I bioactivity progressively increased with increasing insulin resistance, peaked at fasting glucose levels just below 7.0 mmol/l, and dropped at higher glucose levels. Mean IGF-I bioactivity peaked when three criteria of the metabolic syndrome were present and then declined significantly when five criteria of the metabolic syndrome were present. CONCLUSIONS-We observed that IGF-I bioactivity was related to insulin sensitivity, insulin levels, and the metabolic syndrome. Our study suggests that there exists an inverse U-shaped relationship between IGF-I bioactivity and number of components of the metabolic syndrome. This observation contrasts with previous results reporting an inverse relationship between total IGF-I and components of the metabolic syndrome. Diabetes 59:505-508, 2010

Background: Rapid postnatal weight gain is associated with obesity and type 2 diabetes in later life. The influence of rapid weight gain on body composition in early infancy is still unknown and the critical periods of weight gain for later disease are debated. Aims: To investigate the effect of birth weight and rapid weight gain on body composition in the first 6 months of life. Study design: The Generation R Study, a population-based prospective cohort study from fetal life onwards. Subjects and outcome measures: We measured body fat and fat distribution by skinfold thickness at the age of 6 weeks and 6 months in 909 Dutch term infants. Analyses were adjusted for current body mass index, sex and maternal socioeconomic status, pre-pregnancy body mass index, height and duration of breastfeeding. Results: Upward postnatal weight percentile change was associated with increased skinfold thickness, percentage body fat at 6 weeks and 6 months and a larger truncal/peripheral fat ratio at 6 months (p

Background The aim of this study is to examine whether cardiac size and function track in early childhood and are associated with fetal and early postnatal growth and blood flow characteristics. Methods This study was embedded in a population-based prospective cohort study from fetal life onward. Fetal growth and fetal and placental blood flow parameters in second and third trimester of pregnancy were measured by ultrasound and Doppler. Left cardiac structures and shortening fraction were measured postnatally at the ages of 1.5, 6, and 24 months. Analyses were based on 1,001 children. Results Left ventricular mass tended to remain in the lowest and highest quartiles from the age of 1.5 to 24 months (odds ratio 1.70, 95% confidence interval [0] 1.10-2.63) and 2.15 (95% Cl 1.41-3.30), respectively. Similar results were found for aortic root diameter and left atrial diameter. Birth weight was positively associated with aortic root diameter (0.08 mm, 95% Cl 0.01-0.17; per SD increase) and left ventricular mass (0.65 g, 95% Cl 0.09-1.21; per SD increase). Resistance indices of the umbilical and uterine arteries showed weak tendencies toward inverse associations with left cardiac structures. Fetal cardiac output was positively associated with both left atrial diameter (increase of 1.96 mm, 95% Cl 1.28-2.64; per mL/min increase) and left ventricular mass (increase of 1.79 g, 95% CI 0.35-3.22; per mL/min increase). Conclusions This study suggest moderate tracking of left cardiac structures during the first 2 years and that small size and hemodynamic variations in fetal life have consequences for postnatal cardiac size and function. (Am Heart J 2009; 158:71-7.)

We aimed to examine the associations of maternal anthropometrics with fetal weight measured in different periods of pregnancy and with birth outcomes. Population-based birth cohort study. Data of pregnant women and their children in Rotterdam, the Netherlands. In 8541 mothers, height, prepregnancy body mass index (BMI) and gestational weight gain were available. Fetal growth was measured by ultrasound in mid- and late pregnancy. Regression analyses were used to assess the impact of maternal anthropometrics on fetal weight and birth outcomes. Fetal weight and birth outcomes: weight (grams) and the risks of small (< 5th percentile) and large (> 95th percentile) size for gestational age at birth. Maternal BMI in pregnancy was positively associated with estimated fetal weight during pregnancy. The effect estimates increased with advancing gestational age. All maternal anthropometrics were positively associated with fetal size (P-values for trend < 0.01). Mothers with both their prepregnancy BMI and gestational weight gain quartile in the lowest and highest quartiles showed the highest risks of having a small and large size for gestational age child at birth, respectively. The effect of prepregnancy BMI was strongly modified by gestational weight gain. Fetal growth is positively affected by maternal BMI during pregnancy. Maternal height, prepregnancy BMI and gestational weight gain are all associated with increased risks of small and large size for gestational age at birth in the offspring, with an increased effect when combined.

OBJECTIVE - To investigate the relation between total fish, type of fish (lean and fatty), and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake and risk of type 2 diabetes in a population-based cohort. RESEARCH DESIGN AND METHODS - The analysis included 4,472 Dutch participants aged >= 55 years without diabetes at baseline. Dietary intake was assessed with a semiquantitative food frequency questionnaire. Hazard ratios (relative risk [RR]) with 95% CIs were used to examine risk associations adjusted for age, sex, lifestyle, and nutritional factors. RESULTS - After 15 years of follow-up, 463 participants developed type 2 diabetes. Median fish intake, mainly lean fish (81%), was 10 g/day. Total fish intake was associated positively with risk of type 2 diabetes; the RR was 1.32 (95% Cl 1.02-1.70) in the highest total fish group (>= 28 g/day) compared with that for non-fish eaters (P-trend = 0.04). Correspondingly, lean fish intake tended to be associated positively with type 2 diabetes (RR highest group [>= 23 g/day] 1.30 [95% CI 1.01-1..68]; P-trend = 0.06), but fatty fish was not. No association was observed between EPA and DHA intake and type 2 diabetes (RR highest group [>= 149.4 mg/day] 1.22 [0.97-1.53]). With additional adjustment for intake of selenium, cholesterol, and vitamin D, this RR decreased to 1.05 (0.80-1.38; P-trend = 0.77). CONCLUSIONS - The findings do not support a beneficial effect of total fish, type of fish, or EPA and DHA intake on the risk of type 2 diabetes. Alternatively, other dietary components, such as selenium, and unmeasured contaminants present in fish might explain our results.

OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all-cause mortality in elderly people. DESIGN: Prospective Study. SETTING: Community based. PARTICIPANTS: Five thousand sixty-four subjects from the Rotterdam study aged 55 and older. MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mmHg or more or a decline in diastolic blood pressure of 10 mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing. RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow-up, 668 subjects had coronary heart disease (CHD) (mean follow-up 6.0 +/- 3.5 years), and 1,835.subjects died (mean follow-up period 7.8 +/- 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR) = 1.31, 95% confidence interval (CI) = 1.08-1.57) and all-cause mortality (HR = 1.22, 95% CI = 1.09-1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all-cause mortality were 1.80 (95% Cl 1.25-2.60), 1.13 (0.89-1.42), and 1.27 (95% Cl = 1.11-1.44), in the first, second, and third tertile of age, respectively. CONCLUSION: Orthostatic hypotension increases the risk of CHD and all-cause mortality in elderly people. I-lie risk of CVD and mortality is strongest in younger and very old subjects.

Evidence by post-mortem and animal studies suggests that matrix metalloprotemases (MMPs) may play an important role in the pathophysiology of Alzheimer's disease (AD) through degradation of amyloid beta. We investigated in 5999 elderly whether MMP3-haplotypes are associated with cognitive performance over time, dementia and AD. We also explored the association of MMP-3 haplotypes with changes in hippocampal volume and severity of periventricular and subcortical white matter lesions (WML). There was no association between any individual polymorphism or MMP-3 haplotypes and performance in MMSE over time, dementia or AD, and there was no association between MMP-3 genotypes or haplotypes with hippocampal volume or severity of periventricular or subcortical WML. These associations did not differ between strata of APOE epsilon 4 genotype. Our observations do not suggest that variation in the MMP3 gene is causally involved in dementia or AD. (C) 2007 Elsevier Inc. All rights reserved.

OBJECTIVE-Prediction of type 2 diabetes based on genetic testing might improve identification of high-risk subjects. Genome-wide association (GWA) studies identified multiple new genetic variants that associate with type 2 diabetes. The predictive value of genetic testing for prediction of type 2 diabetes in the general population is unclear. RESEARCH DESIGN AND METHODS-We investigated 18 polymorphisms from recent GWA studies on type 2 diabetes in the Rotterdam Study, a prospective, population-based study among homogeneous Caucasian individuals of 55 years and older (genotyped subjects, n = 6,544; prevalent cases, n = 686; incident cases during follow-up, n = 601; mean follow-up 10.6 years). The predictive value of these polymorphisms was examined alone and in addition to clinical characteristics using logistic and Cox regression analyses. The discriminative accuracy of the prediction models was assessed by the area under the receiver operating characteristic curves (AUCs). RESULTS-Of the 18 polymorphisms, the ADAMYS9, CDKAL1, CDKN2A/B-rs1412829, FTO, IGF2BP2, JAZF1, SLC30A8, TCF7L2, and WFS1 variants were associated with type 2 diabetes risk in our population. The AUC was 0.60 (95% Cl 0.57-0.63) for prediction based on the genetic polymorphisms; 0.66 (0.63-0.68) for age, sex, and BMI; and 0.68 (0.66-0.71) for the genetic polymorphisms and clinical characteristics combined. CONCLUSIONS-We showed that 9 of 18 well-established genetic risk variants were associated with type 2 diabetes in a population-based study. Combining genetic variants has low predictive value for future type 2 diabetes at a population-based level. The genetic polymorphisms only marginally improved the prediction of type 2 diabetes beyond clinical characteristics. Diabetes 57:3122-3128, 2008