Jolanda M. A. Boer

Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study.

AIMS A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study. METHODS AND RESULTS After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65-0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92-1.00, P for trend = 0.033). CONCLUSION Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear.

The challenge for genetic epidemiologists: how to analyze large numbers of SNPs in relation to complex diseases

Genetic epidemiologists have taken the challenge to identify genetic polymorphisms involved in the development of diseases. Many have collected data on large numbers of genetic markers but are not familiar with available methods to assess their association with complex diseases. Statistical methods have been developed for analyzing the relation between large numbers of genetic and environmental predictors to disease or disease-related variables in genetic association studies.In this commentary we discuss logistic regression analysis, neural networks, including the parameter decreasing method (PDM) and genetic programming optimized neural networks (GPNN) and several non-parametric methods, which include the set association approach, combinatorial partitioning method (CPM), restricted partitioning method (RPM), multifactor dimensionality reduction (MDR) method and the random forests approach. The relative strengths and weaknesses of these methods are highlighted.Logistic regression and neural networks can handle only a limited number of predictor variables, depending on the number of observations in the dataset. Therefore, they are less useful than the non-parametric methods to approach association studies with large numbers of predictor variables. GPNN on the other hand may be a useful approach to select and model important predictors, but its performance to select the important effects in the presence of large numbers of predictors needs to be examined. Both the set association approach and random forests approach are able to handle a large number of predictors and are useful in reducing these predictors to a subset of predictors with an important contribution to disease. The combinatorial methods give more insight in combination patterns for sets of genetic and/or environmental predictor variables that may be related to the outcome variable. As the non-parametric methods have different strengths and weaknesses we conclude that to approach genetic association studies using the case-control design, the application of a combination of several methods, including the set association approach, MDR and the random forests approach, will likely be a useful strategy to find the important genes and interaction patterns involved in complex diseases.

Frequent Mutation in the ABCC6 Gene (R1141X) Is Associated With a Strong Increase in the Prevalence of Coronary Artery Disease

Background—Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD. Methods and Results—To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age- and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%;P <0.001). Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20, P = 0.001). Conclusion—The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD.

Validity of coronary heart diseases and heart failure based on hospital discharge and mortality data in the Netherlands using the cardiovascular registry Maastricht cohort study

Incidence rates of cardiovascular diseases are often estimated by linkage to hospital discharge and mortality registries. The validity depends on the quality of the registries and the linkage. Therefore, we validated incidence rates of coronary heart disease (CHD), acute myocardial infarction, unstable angina pectoris, and heart failure, estimated by this method, against the disease registry of the cardiovascular registry Maastricht cohort study. The cohort consists of 21,148 persons, born between 1927 and 1977, who were randomly sampled from Maastricht and surrounding communities in 1987–1997. Incident cases were identified by linkage to the Netherlands causes of death registry and either the hospital discharge registry (HDR) or the cardiology information system (CIS) of the University Hospital Maastricht. Sensitivities and positive predictive values were calculated using the CIS-based registry as gold standard. Relatively high sensitivities and positive predictive values were found for CHD (72 and 91%, respectively) and acute myocardial infarction (84 and 97%, respectively). These values were considerably lower for unstable angina pectoris (53 and 78%, respectively) and heart failure (43 and 80%, respectively). A substantial number of cases (14–47%) were found only in the CIS-based registry, because they were missed or miscoded in the HDR-based registry. As a consequence, the incidence rates in the HDR-based registry were considerably lower than in the CIS-based registry, especially for unstable angina pectoris and heart failure. Incidence rates based on hospital discharge and mortality data may underestimate the true incidence rates, especially for unstable angina pectoris and heart failure.

Tea and Coffee Consumption and Cardiovascular Morbidity and Mortality

Objective—To examine the associations of coffee and tea consumption with risk of morbidity and mortality of stroke and coronary heart disease (CHD) and with all-cause mortality. Methods and Results—Coffee and tea consumption were assessed with a validated food-frequency questionnaire, and 37 514 participants were observed for 13 years for the occurrence of cardiovascular morbidity and mortality. A U-shaped association between coffee and CHD was found, with the lowest hazard ratio (HR [95% CI]) for 2.1 to 3.0 cups per day (0.79 [0.65 to 0.96]; Ptrend=0.01). Tea was inversely associated with CHD, with the lowest HR (95% CI) for more than 6.0 cups per day (0.64 [0.46 to 0.90]; Ptrend=0.02). No associations between tea or coffee and stroke were found (Ptrend=0.63 and Ptrend=0.32, respectively). Although not significant, coffee slightly reduced the risk for CHD mortality (HR, 0.64; 95% CI, 0.37 to 1.11; Ptrend=0.12) for 3.1 to 6.0 cups per day. A U-shaped association between tea and CHD mortality was observed, with an HR of 0.55 (95% CI, 0.31 to 0.97; Ptrend=0.03) for 3.1 to 6.0 cups per day. Neither coffee nor tea was associated with stroke (Ptrend=0.22 and Ptrend=0.74, respectively) and all-cause mortality (Ptrend=0.33 and Ptrend=0.43, respectively). Conclusion—High tea consumption is associated with a reduced risk of CHD mortality. Our results suggest a slight risk reduction for CHD mortality with moderate coffee consumption and strengthen the evidence on the lower risk of CHD with coffee and tea consumption.

Dietary n−3 and n−6 polyunsaturated fatty acid intake interacts with FADS1 genetic variation to affect total and HDL-cholesterol concentrations in the Doetinchem Cohort Study

BACKGROUND The delta-5 and delta-6 desaturases, encoded by the FADS1 and FADS2 genes, are rate-limiting enzymes in polyunsaturated fatty acid (PUFA) biosynthesis. Single nucleotide polymorphisms in the FADS gene cluster region have been associated with both PUFA concentrations in plasma or erythrocyte membrane phospholipids and cholesterol concentrations in recent genome-wide association studies. OBJECTIVE We examined whether genetic variations in the FADS gene cluster region interact with dietary intakes of n-3 (omega-3) and n-6 (omega-6) PUFAs to affect plasma total, HDL-, and non-HDL-cholesterol concentrations. DESIGN Dietary intakes of n-3 and n-6 PUFAs, plasma concentrations of total and HDL cholesterol, and rs174546, rs482548, and rs174570 in the FADS gene cluster region were measured in 3575 subjects in the second survey of the Doetinchem Cohort Study. RESULTS Significant associations between rs174546 genotypes and total and non-HDL-cholesterol concentrations were observed in the group with a high intake of n-3 PUFAs (> or =0.51% of total energy; P = 0.006 and 0.047, respectively) but not in the low-intake group (P for interaction = 0.32 and 0.51, respectively). The C allele was associated with high total and non-HDL-cholesterol concentrations. Furthermore, the C allele was significantly associated with high HDL-cholesterol concentrations in the group with a high intake of n-6 PUFAs (> or =5.26% of total energy, P = 0.004) but not in the group with a low intake (P for interaction = 0.02). CONCLUSION Genetic variation in the FADS1 gene potentially interacts with dietary PUFA intakes to affect plasma cholesterol concentrations, which should be investigated further in other studies.

Eating out of home: energy, macro- and micronutrient intakes in 10 European countries. The European Prospective Investigation into Cancer and Nutrition

Objectives:To assess the contribution of out-of-home (OH) energy and nutrient intake to total dietary intake, and to compare out- versus in-home nutrient patterns among 27 centres in 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Methods:Between 1995 and 2000, 36 034 participants aged between 35–74 years completed a standardized 24-h dietary recall using a software programme (EPIC-Soft) that recorded the place of food/drink consumption. Eating OH was defined as the consumption of foods and beverages anywhere other than in household premises, irrespective of the place of purchase/preparation. Nutrient intakes were estimated using a standardized nutrient database. Mean intakes were adjusted for age and weighted by season and day of recall.Results:Among women, OH eating contributed more to total fat intake than to intakes of protein and carbohydrates. Among both genders, and particularly in southern Europe, OH eating contributed more to sugar and starch intakes and less to total fibre intake. The contribution of OH eating was also lower for calcium and vitamin C intakes. The composition of diet at home was different from that consumed out of home in southern countries, but was relatively similar in the north.Conclusions:In northern Europe, OH and in-home eating are homogeneous, whereas southern Europeans consider OH eating as a distinctive occasion. In most centres, women selected more fat-rich items when eating out.

Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.

We assessed the dose-response relations within a low range of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and fish intake on fatal coronary heart disease (CHD) and nonfatal myocardial infarction (MI). In a Dutch population-based cohort study, EPA+DHA and fish intake were assessed at baseline among 21,342 participants aged 20-65 y with no history of MI or stroke. Hazard ratios were calculated with Cox proportional-hazard models. During 9-14 y of follow-up (mean 11.3 y), 647 participants (3%) died, of which 82 of CHD. Fatal CHD mainly comprised MI (64 cases). In total, 252 participants survived an MI. Median intakes in quartiles of EPA+DHA were 40, 84, 151, and 234 mg/d. Medians of fish consumption in quartiles were 1.1, 4.2, 10.7, and 17.3 g/d. Compared with the lowest quartile of EPA+DHA, participants in the top quartile had a 49% lower risk of fatal CHD (95% CI: 6-73%) and a 62% lower risk of fatal MI (95% CI: 23-81%). We observed inverse dose-response relations for EPA+DHA intake and fatal CHD (P-trend = 0.05) and fatal MI (P-trend = 0.01). Results were similar for fish consumption. Nonfatal MI was not associated with EPA+DHA or fish intake. In conclusion, in populations with a low fish consumption, EPA+DHA and fish may lower fatal CHD and MI risk in a dose-responsive manner. Low intakes of EPA+DHA or fish do not seem to protect against nonfatal MI.

Body mass index and waist circumference predict both 10-year nonfatal and fatal cardiovascular disease risk: study conducted in 20 000 Dutch men and women aged 20–65 years

Aims Body mass index (BMI) and waist circumference (WC) are both predictors of cardiovascular diseases (CVD). We compared absolute risk, hazard ratio (HR), and population attributable risk of nonfatal and fatal CVD for BMI and WC in a large prospective cohort study with an average follow-up of 10 years. Methods and results Anthropometric data were measured between 1993 and 1997 in a general population sample of over 20000 men and women aged 20–65 years in the Netherlands. All risks were adjusted for age and sex. Absolute risk of nonfatal CVD was on average 10 times higher than that of fatal CVD. In obese respondents (BMI ≥ 30 kg/m2), relative risk of fatal CVD was four-fold higher [HR = 4.0 95% confidence interval (CI) = 2.4–6.6], whereas risk of nonfatal CVD was two-fold higher (HR = 1.8 95% CI = 1.6–2.2) than in normal-weight respondents. Similar associations were observed for WC (≥ 88 vs. >80 cm in women and ≥ 102 vs. 94 cm in men). In persons with overweight or obesity (BMI ≥ 25 kg/m2), half of all fatal CVD (attributable risk = 54%, 95% CI = 30–70) and a quarter of nonfatal CVD was ascribed to their overweight. On the population level, one-third of all fatal CVD cases could be attributed to overweight and obesity (population attributable risk =35%, 95% CI =14–52), and about one in seven of nonfatal CVD cases. Conclusion The associations of BMI and WC with CVD risk were equally strong. Overweight and obesity had a stronger impact on fatal CVD than on nonfatal CVD.

High HDL cholesterol does not protect against coronary artery disease when associated with combined cholesteryl ester transfer protein and hepatic lipase gene variants

Cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are two HDL modifying proteins that have both pro- and anti-atherogenic properties. We hypothesized that CETP and HL synergistically affect HDL cholesterol and atherosclerotic risk. To test our hypothesis, we analysed the genotype frequencies of CETP Taq1B (rs708272) and LIPC-514C/T (rs1800588) polymorphisms in male coronary artery disease patients (CAD; n=792) and non-symptomatic controls (n=539). Cases and controls had similar allele frequencies, but the occurrence of the combined genotypes differed (p=0.027). In CAD patients, 1.3% had the CETP-B2B2/LIPC-TT genotype, with only 0.2% in controls (p=0.033). The presence of the CETP lowering B2 allele and the HL lowering LIPC-T allele synergistically increased HDL cholesterol from 0.87+/-0.19 mmol/L in the B1B1/CC (n=183) to 1.21+/-0.25 mmol/L in the B2B2/TT carriers (n=10). The B1B1/CC carriers had an increased CAD risk (OR 1.4; p=0.025). Despite their high HDL cholesterol, the B2B2/TT individuals also had an increased CAD risk (OR 3.7; p=0.033). In a 2-year follow up, the loss of coronary artery lumen diameter in these patients was higher than in all other patients combined (0.34+/-0.70 versus 0.10+/-0.29 mm; p=0.044). We conclude that a high HDL cholesterol does not protect against coronary artery disease when associated with combined CETP- and HL-lowering gene variants.