Multiple studies have identified single-nucleotide polymorphisms (SNPs) that are associated with coronary heart disease (CHD). We examined whether SNPs selected based on predefined criteria will improve CHD risk prediction when added to traditional risk factors (TRFs).
SNPs were selected from the literature based on association with CHD, lack of association with a known CHD risk factor, and successful replication. A genetic risk score (GRS) was constructed based on these SNPs. Cox proportional hazards model was used to calculate CHD risk based on the Atherosclerosis Risk in Communities (ARIC) and Framingham CHD risk scores with and without the GRS.
The GRS was associated with risk for CHD (hazard ratio [HR] = 1.10; 95% confidence interval [CI]: 1.07–1.13). Addition of the GRS to the ARIC risk score significantly improved discrimination, reclassification, and calibration beyond that afforded by TRFs alone in non-Hispanic whites in the ARIC study. The area under the receiver operating characteristic curve (AUC) increased from 0.742 to 0.749 (Δ= 0.007; 95% CI, 0.004–0.013), and the net reclassification index (NRI) was 6.3%. Although the risk estimates for CHD in the Framingham Offspring (HR = 1.12; 95% CI: 1.10–1.14) and Rotterdam (HR = 1.08; 95% CI: 1.02–1.14) Studies were significantly improved by adding the GRS to TRFs, improvements in AUC and NRI were modest.
Addition of a GRS based on direct associations with CHD to TRFs significantly improved discrimination and reclassification in white participants of the ARIC Study, with no significant improvement in the Rotterdam and Framingham Offspring Studies.
Genetics; Risk factors; Coronary disease
Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children, and to assess overlap in variants between different age groups, using genome wide profiling. SNP sets were defined based on a meta-analysis of genome-wide association studies on systolic (SBP) and diastolic blood pressure (DBP) performed by the Cohort for Heart and Aging Research in Genome Epidemiology (CHARGE, n=29,136), using different P-value thresholds for selecting single nucleotide polymorphisms (SNPs). Subsequently, genetic risk scores for SBP and DBP were calculated in an independent adult population (n=2,072) and a child population (n=1,034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age and body mass index. Genetic risk scores, including also many non-genome-wide significant SNPs explained more of the variance than scores based only on very significant SNPs in adults and children. Genetic risk scores significantly explained up to 1.2% (P=9.6*10−8) of the variance in adult SBP and 0.8% (P=0.004) in children. For DBP, the variance explained was similar in adults and children (1.7% (P=8.9*10−10) and 1.4% (P=3.3*10−5) respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.
genome-wide association; genome-wide profiling; genetic risk scores; blood pressure; hypertension
The prevalence of cardiovascular diseases is rising. Therefore, adequate risk prediction and identification of its determinants is increasingly important. The Rotterdam Study is a prospective population-based cohort study ongoing since 1990 in the city of Rotterdam, The Netherlands. One of the main targets of the Rotterdam Study is to identify the determinants and prognosis of cardiovascular diseases. Case finding in epidemiological studies is strongly depending on various sources of follow-up and clear outcome definitions. The sources used for collection of data in the Rotterdam Study are diverse and the definitions of outcomes in the Rotterdam Study have changed due to the introduction of novel diagnostics and therapeutic interventions. This article gives the methods for data collection and the up-to-date definitions of the cardiac outcomes based on international guidelines, including the recently adopted cardiovascular disease mortality definitions. In all, detailed description of cardiac outcome definitions enhances the possibility to make comparisons with other studies in the field of cardiovascular research and may increase the strength of collaborations.
Cardiovascular disease; Coronary heart disease; Myocardial infarction; Coronary revascularization; Heart failure; Atrial fibrillation; Unrecognized myocardial infarction; Sudden cardiac death; Diagnostic guidelines; Epidemiologic methods; Population-based
As life expectancy continually increases, it is imperative to identify determinants of survival to the extreme end of the lifespan and more importantly to identify factors that increase the chance of survival free of major morbidities. As such, the current study assessed 45 common disease factors as predictors of survival and morbidity-free survival to age 85 years. Within the Rotterdam Study, a population-based cohort, we evaluated morbidity-free participants who were able to attain age 85 within the study duration (n = 2,008). Risk factors were assessed at baseline (1990–1993), and mortality and morbidities were then collected continuously until mortality or the occurrence of their 85th birthday (average time of 7.9 years). Risk factors included demographic and lifestyle variables, health and morbidity indicators and physiological makers. Major morbidities examined included dementia, cancer, cerebrovascular accident, heart failure and myocardial infarction. Logistic regression analyses demonstrated that many of the variables were independently predictive for survival and for morbidity-free ageing to 85 years. These included being female, absence of left ventricular abnormalities, stable body weight, unimpaired instrumental activities of daily living, lower C-RP levels and higher levels of femoral neck bone mineral density and albumin. Relative to non-survival, predictors were stronger for morbidity-free survival than for total survival or survival with morbidity. This suggests that lifespan and healthy survival to older age can be relatively well predicted. Understanding predictors of a long and healthy lifespan is vital for developing primary and secondary preventions to help improve the quality of life of older adults and for reducing the financial burden of the rapidly escalating ageing population.
Healthy ageing; Oldest-old; Risk factors; Mortality; Morbidity
Maternal and fetal characteristics are important determinants of fetal growth potential, and should ideally be taken into consideration when evaluating fetal growth variation. We developed a model for individually customised growth charts for estimated fetal weight, which takes into account physiological maternal and fetal characteristics known at the start of pregnancy. We used fetal ultrasound data of 8,162 pregnant women participating in the Generation R Study, a prospective, population-based cohort study from early pregnancy onwards. A repeated measurements regression model was constructed, using backward selection procedures for identifying relevant maternal and fetal characteristics. The final model for estimating expected fetal weight included gestational age, fetal sex, parity, ethnicity, maternal age, height and weight. Using this model, we developed individually customised growth charts, and their corresponding standard deviations, for fetal weight from 18 weeks onwards. Of the total of 495 fetuses who were classified as small size for gestational age (<10th percentile) when fetal weight was evaluated using the normal population growth chart, 80 (16%) were in the normal range when individually customised growth charts were used. 550 fetuses were classified as small size for gestational age using individually customised growth charts, and 135 of them (25%) were classified as normal if the unadjusted reference chart was used. In conclusion, this is the first study using ultrasound measurements in a large population-based study to fit a model to construct individually customised growth charts, taking into account physiological maternal and fetal characteristics. These charts might be useful for use in epidemiological studies and in clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-011-9629-7) contains supplementary material, which is available to authorized users.
Customised fetal growth curves; Ultrasound; Fetal weight; Biometry; Ethnicity; Maternal anthropometrics
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.
Biomarkers; Cardiovascular diseases; Cohort study; Dermatological diseases; Endocrine diseases; Epidemiologic methods; Genetic epidemiology; Liver diseases; Neurological diseases; Oncology; Ophthalmic diseases; Pharmacoepidemiology; Renal diseases; Psychiatric diseases; Respiratory diseases
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.
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.
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.
To study consumption of major dietary antioxidants in relation to long-term risk of dementia.
DESIGN AND SETTING
The Rotterdam Study, a population-based, prospective cohort study in the Netherlands.
A total of 5,395 participants, aged 55+ years, who were free of dementia and provided dietary information at study baseline.
MAIN OUTCOME MEASURES
Incidence of dementia and Alzheimer’s disease (AD), based on internationally accepted criteria, in relation to dietary intake of vitamin E, vitamin C, beta carotene, and flavonoids.
During an average follow-up period of 9.6 years, dementia developed in 465 participants, of whom 365 were diagnosed with AD. In multivariate models adjusted for age, education, APOE ε4 genotype, total energy intake, alcohol intake, smoking habits, body-mass index (BMI), and supplement use, higher intake of vitamin E at baseline was associated with a lower long-term risk of dementia (p-trend=0.02). Compared to participants in the lowest tertile of vitamin E intake, those in the highest tertile were 25% less likely to develop dementia (HR, 0.75; 95% CI, 0.59–0.95 with adjustment for potential confounders). Dietary intakes of vitamin C, beta carotene, and flavonoids were not associated with dementia risk (after multivariate adjustment, p-trend=1.0 for both vitamin C and beta carotene and p-trend=0.6 for flavonoids). Results were similar when AD risk was specifically examined.
Higher intake of foods rich in vitamin E may modestly reduce long-term risk of dementia and AD.
Objective. To investigate whether the Glycemic Index (GI) or Glycemic Load (GL) of a diet is associated with C-reactive Protein (CRP) and risk of type 2 diabetes in a prospective study. Materials and Methods. Our analysis included 4,366 participants who did not have diabetes at baseline. During follow-up 456 diabetes cases were confirmed. Dietary GI and GL were derived from a food-frequency questionnaire and its association with CRP was examined cross-sectionally using linear regression models. The association of GI and GL with diabetes incidence was examined using Cox proportional hazard models. Results. GL, but not GI, was associated with lnCRP at baseline (bGL = 0.11 per 50 units; P = .01). When comparing the highest to the lowest tertile of GI with respect to diabetes incidence, a Relative Risk (RR) of 0.95 [95%CI 0.75, 1.21] was found after adjustment for lifestyle and nutritional factors. For GL the RR for diabetes incidence was 1.00 [95%CI 0.74, 1.36]. Additional adjustment for CRP did not change RRs.
Conclusion. Since GI was not associated with CRP and risk of type 2 diabetes, it is unlikely that a high GI diet induces the previously shown positive association between CRP and risk of type 2 diabetes by increasing CRP concentrations.
Coronary artery calcification (CAC) has been proposed to be the underlying mechanism of the increased risk of coronary heart disease with reductions in glomerular filtration rate (GFR). Since renal function diminishes with aging we examined the association between GFR and CAC in the Rotterdam Study, a population-based study of elderly individuals.
The study was performed in 1703 subjects without a history of coronary heart disease. GFR was estimated using the modification of diet in renal disease equation. We used analysis of covariance to test for mean differences in CAC between GFR tertiles.
The mean CAC scores in the middle and lowest GFR tertile did not significantly differ from the mean CAC score in the highest GFR tertile (geometric mean CAC score 4.1 and 4.3 vs 4.2). In a multivariable model the mean CAC score did also not differ between the GFR tertiles. As the interaction term between age and GFR was significant (P = 0.037), we divided the population in two age categories based on median age of 70 years. Below 70 years, the mean CAC scores did not differ between the GFR tertiles. Above median age, mean CAC score in the lowest GFR tertile was significantly higher than the mean CAC score in the highest tertile in a multivariable model (CAC 4.9 vs 4.5, p = 0.010).
In this population-based study we observed that the association between CAC and GFR is modified by age. In participants at least 70 years of age, a decrease in GFR was associated with increased CAC.
SIRT1 has pleiotropic metabolic functions. We investigated whether SIRT1 genetic variation is associated with obesity.
RESEARCH DESIGN AND METHODS
In 6,251 elderly subjects from the prospective, population-based Rotterdam Study, three single nucleotide polymorphisms (SNPs) in the SIRT1 gene were studied in relation to BMI and risk of obesity (BMI ≥30 kg/m2) and prospectively with BMI change after 6.4 years of follow-up. We used cross-sectional data from 2,347 participants from the Erasmus Rucphen Family (ERF) study for replication.
Minor alleles of rs7895833 (G = 20.2%) and rs1467568 (A = 36.8%) were associated with lower BMI in the Rotterdam Study (P = 0.02 and 0.04) and in the replication cohort ERF study (P = 0.03 and 0.008) and in both studies combined (P = 0.002 for both SNPs), with a 0.2–0.4 kg/m2 decrease in BMI per allele copy. Carriers of these alleles had 13–18% decreased risk of obesity (for rs7895833 in the Rotterdam Study: odds ratio 0.79 [95% CI 0.67–0.94], P = 0.007; in the ERF study: 0.93 [0.73–1.19], P = 0.37; and in the studies combined 0.87 [0.77–0.97], P = 0.02; for rs1467568 in the Rotterdam Study: 0.80 [0.68–0.94], P = 0.007; in the ERF study: 0.85 [0.72–0.99], P = 0.04; and in the studies combined: 0.82 [0.73–0.92], P = 0.0009). In the Rotterdam Study, the two variants were also associated with a lower BMI increase during 6.4 years of follow-up (P = 0.01 and 0.08).
Two common variants in SIRT1 are associated with lower BMI in two independent Dutch populations. Carriers of these variants have 13–18% decreased risk of obesity and gain less weight over time. The availability of SIRT1 stimulators makes these findings relevant in light of the growing obesity epidemic.
The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5–12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-μm increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.
cohort studies; meta-analysis; retinal vessels; risk; stroke
Common variation within the nitric oxide-1 synthase activator protein (NOS1AP) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.
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.
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% CI 1.02–1.70) in the highest total fish group (≥28 g/day) compared with that for non–fish eaters (Ptrend = 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]; Ptrend = 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; Ptrend = 0.77).
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.
The purpose of the present study is to examine HFE gene mutations in relation to newly diagnosed (incident) coronary heart disease (CHD). In a population-based follow-up study of 7,983 individuals aged 55 years and older, we compared the risk of incident CHD between HFE carriers and non-carriers, overall and stratified by sex and smoking status. HFE mutations were significantly associated with an increased risk of incident CHD in women but not in men (hazard ratio [HR] for women = 1.7, 95% confidence interval [CI] 1.2–2.4 versus HR for men = 0.9, 95% CI 0.7–1.2). This increased CHD risk associated with HFE mutations in women was statistically significant in never smokers (HR = 1.8, 95% CI 1.1–2.8) and current smokers (HR = 3.1, 95% CI 1.4–7.1), but not in former smokers (HR = 1.3, 95% CI 0.7–2.4). HFE mutations are associated with increased risk of incident CHD in women.
HFE mutation; Hemochromatosis; Coronary heart disease; Smoking; Gender
Retinal vessel caliber may be a novel risk marker of coronary heart disease (CHD) risk. However, the gender specific effect, magnitude of association and effect independent of traditional CHD disease risk factors remain unclear.
To determine the association between retinal vessel caliber and risk of CHD.
Relevant studies were identified through MEDLINE (1950 to June 2009) and EMBASE (1950 to June 2009) databases.
Studies were included if derived from a general population, retinal vessel caliber was measured from retinal photographs and incident CHD events were documented.
Six population-based prospective cohort studies were identified and provided data for individual participant meta-analysis.
Proportional hazards models were constructed for retinal vessel caliber and incident CHD in women and men, while adjusting for traditional CHD risk factors. 2,219 (10.0%) incident CHD events were recorded from 22,159 individuals (mean age 62 years) free of CHD followed for 5–14 years. Retinal vessel caliber changes (wider retinal venules and narrower arterioles) were each associated with an increased risk of CHD in women but not men, with pooled multivariable-adjusted hazard ratios of 1.16 (95% confidence interval, CI, 1.06 to 1.26) per 20μm increase in venular caliber, and 1.17 (95% CI, 1.07 to 1.28) per 20μm decrease in arteriolar caliber in women, and 1.02 (95% CI, 0.94 to 1.10) per 20μm increase in venular caliber and 1.02 (95% CI, 0.95, 1.10) per 20μm decrease in arteriolar caliber in men. Higher hazard ratios were found amongst women without hypertension or diabetes.
Error in the measurement of retinal vessel caliber and Framingham variables was not taken into account, and may over or underestimate the true association between retinal vessel caliber and CHD.
Retinal vessel caliber changes were independently associated with an increased risk of CHD events in women.
Despite considerable progress in unravelling the genetic basis of dyslipidemias, most findings are based on families with extreme phenotypes. We studied lipid levels in an extended pedigree ascertained irrespective of phenotype from the population of a recent genetic isolate in the Netherlands. Heritabilities of plasma lipid measures were examined; this analysis also included estimates of the proportion of variance attributable to ApoE genotype. The association between inbreeding and lipids was also considered, as a substantial fraction of the population had known inbreeding. A total of 868 individuals from this pedigree, containing more than 60,000 people over 15 generations, were investigated in this study. Laboratory analysis of these subjects included the determination of fasting plasma lipids. ApoE ɛ2/3/4 status was ascertained using TaqMan assays. Heritabilities for plasma lipids were estimated with adjustments for multiple covariates using SOLAR. Heritabilities for total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides (TG), TC/HDL ratio, and TG/HDL ratio were found to be 0.35, 0.56, 0.30, 0.24, 0.49, and 0.39, respectively. The addition of ApoE genotype in the model significantly decreased these estimates (Δh2 = −0.030, −0.004, −0.054, and −0.006 for TC, HDL, LDL, and TG). In a further analysis, TC and LDL were positively associated with the extent of inbreeding (ptrend = 0.02 and ptrend = 0.05, respectively). These data provide estimates of lipid heritability unbiased due to selection and suggest that this population represents a good opportunity to localize novel genes influencing plasma lipid levels.
ApoE; Cholesterol; Extended pedigree; HDL; Inbreeding; LDL; Triglycerides
It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation. Setting: two independent population-based cohort studies. Participants: 445 male participants (≥55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block. Endpoints: length of the QTc, QT and RR intervals. Analysis: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [−3.4 ms (−6.5; −0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [−0.7 ms (−3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.
Serum testosterone; Ventricular repolarization; QTc interval; RR interval
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 ADAMTS9, 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% CI 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.
QT interval duration reflecting myocardial repolarization on the electrocardiogram is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of 3 genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study. We observed associations at P < 5×10−8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and Mendelian Long QT Syndromes. Associations at five novel loci included 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RIFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4–6.5% of variation in QT interval. Identifying the causal variants and defining their impact on myocardial repolarization may add incrementally to the prevention of sudden cardiac death and drug-induced arrhythmias.
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 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 close to a 1,000 research articles and reports (see www.epib.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.
Biomarkers; Cardiovascular diseases; Cohort study; Endocrine diseases; Epidemiologic methods; Genetic epidemiology; Liver diseases; Neurological diseases; Ophthalmic diseases; Pharmacoepidemiology; Psychiatric diseases; Respiratory diseases
There is growing evidence that not only the total amount of fat, but also the distribution of body fat determines risks for metabolic and cardiovascular disease. Developmental studies on factors influencing body fat distribution have been hampered by a lack of appropriate techniques for measuring intraabdominal fat in early life. Sonography, which is an established method for assessing abdominal fat distribution in adults, has not yet been evaluated in infants. To adapt the sonographic measurement of abdominal fat distribution to infants and study its reliability. The Generation R study, a population-based prospective cohort study. We included 212 one- and 227 two-year old Dutch infants in the present analysis. Sixty-two infants underwent replicate measurements to assess reproducibility. We developed a standardized protocol to measure the thickness of (1) subcutaneous and (2) preperitoneal fat in the upper abdomen of infants. To this end we defined infancy specific measurement areas to quantify fat thickness. Reproducibility of fat measurements was good to excellent with intraclass correlation coefficients of 0.93–0.97 for intra-observer agreement and of 0.89–0.95 for inter-observer agreement. We observed a pronounced increase in preperitoneal fat thickness in the second year of life while subcutaneous fat thickness increased only slightly, resulting in an altered body fat distribution. Gender did not significantly influence fat distribution in the first two years of life. Our age specific protocol for the sonographic measurement of central subcutaneous and preperitoneal fat is a reproducible method that can be instrumental for investigating fat distribution in early life.
Abdominal fat distribution; Body composition; Infancy; Intraabdominal fat; Sonography; Visceral fat
Objective To investigate the relationship between the apolipoprotein E (APOE) gene and the risk of mortality in normal weight, overweight and obese individuals. Methods and Results In a population-based study of 7,983 individuals aged 55 years and older, we compared the risks of all-cause and coronary heart disease (CHD) mortality by APOE genotype, both overall and in subgroups defined by body mass index (BMI). We found significant evidence for interaction between APOE and BMI in relation to total cholesterol (p = 0.04) and HDL cholesterol (p < 0.001). Overall, APOE*2 carriers showed a decreased risk of all-cause mortality. Analyses within BMI strata showed a beneficial effect of APOE*2 only in normal weight persons (adjusted hazard ratio (HR) 0.7[95% CI 0.5–0.9]). APOE*2 was not associated with a lower risk of all-cause mortality in overweight or obese persons. The effect of APOE*2 in normal weight individuals tended to be due to the risk of CHD mortality (adjusted HR 0.5 [95% CI 0.2–1.2]). Conclusion The APOE*2 allele confers a lower risk of all-cause mortality only to normal weight individuals.
APOE; BMI; Cholesterol; Mortality; CHD mortality
The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in the Netherlands. The study targets cardiovascular, neurological, ophthalmological and endocrine diseases. As of 2008 about 15,000 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in some 600 research articles and reports (see http://www.epib.nl/rotterdamstudy). This article gives the reasons for the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
Alzheimer disease; Cohort study; Dementia; Diabetes; Genome wide analysis; Glaucoma; Heart failure; Macular degeneration; Myocardial infarction; Osteoporosis; Parkinson disease; Pharmaco-epidemiology; Stroke
Background Dietary electrolytes influence blood pressure, but their effect on clinical outcomes remains to be established. We examined sodium and potassium intake in relation to cardiovascular disease (CVD) and mortality in an unselected older population. Methods A case–cohort analysis was performed in the Rotterdam Study among subjects aged 55 years and over, who were followed for 5 years. Baseline urinary samples were analyzed for sodium and potassium in 795 subjects who died, 206 with an incident myocardial infarction and 181 subjects with an incident stroke, and in 1,448 randomly selected subjects. For potassium, dietary data were additionally obtained by food-frequency questionnaire for 78% of the cohort. Results There was no consistent association of urinary sodium, potassium, or sodium/potassium ratio with CVD and all-cause mortality over the range of intakes observed in this population. Dietary potassium estimated by food frequency questionnaire, however, was associated with a lower risk of all-cause mortality in subjects initially free of CVD and hypertension (RR = 0.71 per standard deviation increase; 95% confidence interval: 0.51–1.00). We observed a significant positive association between urinary sodium/potassium ratio and all-cause mortality, but only in overweight subjects who were initially free of CVD and hypertension (RR = 1.19 (1.02–1.39) per unit). Conclusion The effect of sodium and potassium intake on CVD morbidity and mortality in Western societies remains to be established.
Salt; Sodium; Potassium; Mortality; Cardiovascular disease; Myocardial infarction; Stroke; Population-based