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Abstract  EPIC-Heart is the cardiovascular component of the European Prospective Investigation into Cancer and Nutrition (EPIC), a multi-centre prospective cohort study investigating the relationship between nutrition and major chronic disease outcomes. Its objective is to advance understanding about the separate and combined influences of lifestyle (especially dietary), environmental, metabolic and genetic factors in the development of cardiovascular diseases by making best possible use of the unusually informative database and biological samples in EPIC. Between 1992 and 2000, 519,978 participants (366,521 women and 153,457 men, mostly aged 35–70 years) in 23 centres in 10 European countries commenced follow-up for cause- specific mortality, cancer incidence and major cardiovascular morbidity. Dietary information was collected with quantitative questionnaires or semi-quantitative food frequency questionnaires, including a 24-h dietary recall sub-study to help calibrate the dietary measurements. Information was collected on physical activity, tobacco smoking, alcohol consumption, occupational history, socio-economic status, and history of previous illnesses. Anthropometric measurements and blood pressure recordings were made in the majority of participants. Blood samples were taken from 385,747 individuals, from which plasma, serum, red cells, and buffy coat fractions were separated and aliquoted for long-term storage. By 2004, an estimated 10,000 incident fatal and non-fatal coronary and stroke events had been recorded. The first cycle of EPIC-Heart analyses will assess associations of coronary mortality with several prominent dietary hypotheses and with established cardiovascular risk factors. Subsequent analyses will extend this approach to non-fatal cardiovascular outcomes␣and to further dietary, biochemical and genetic factors. [ABSTRACT FROM AUTHOR]

Background Blood concentrations of fibrinogen have been associated with coronary heart disease risk in epidemiological studies, but it is uncertain whether this association is causal or reflects residual confounding by other risk factors. We investigated the relationship between the single nucleotide polymorphism at position −148 in the beta-fibrinogen gene promoter (β − 148C/T), blood fibrinogen levels, and risk of myocardial infarction (MI) in sufficiently large numbers of coronary disease cases to reliably address this question.Methods Genotyping and measurement of blood fibrinogen concentration were carried out in 4685 cases of confirmed MI and 3460 controls with no history of coronary disease. A meta-analysis of ISIS and 19 other studies of beta-fibrinogen genotypes involving a total of 12 220 coronary disease cases and 18 716 controls was conducted.Results Among the ISIS controls, mean plasma fibrinogen concentrations with the C/C, C/T and T/T genotypes were 3.34 (SE 0.015), 3.48 (0.022), and 3.60 (0.064) g/l, respectively, corresponding to an increase of 0.14 (0.024) g/l per T allele (trend P < 0.0001). In the case–control comparison, 0.14 g/l higher usual plasma fibrinogen concentration was associated with an age-adjusted and sex-adjusted risk ratio for MI of 1.17 [95% confidence interval (95% CI) 1.14–1.19; P < 0.0001]. But, after further adjustment for smoking, body mass index, and plasma apolipoprotein B/A1 ratio, this risk ratio fell to 1.03 (95% CI 1.00–1.05; P = 0.05). Moreover, fibrinogen genotype was not significantly associated with MI incidence: risk ratio of 1.06 (95% CI 0.96–1.16) per higher-fibrinogen allele in ISIS alone and of 1.00 (95% CI 0.95–1.04) per allele in the meta-analysis.Conclusions Genotypes that produce lifelong differences in fibrinogen concentrations do not materially influence coronary disease incidence. As these genotype-dependent differences in fibrinogen were allocated randomly at conception (Mendelian randomization), this association is not likely to be confounded by other factors. Consequently, these genetic results provide strong evidence that long-term differences in fibrinogen concentrations are not a major determinant of coronary disease risk. [ABSTRACT FROM AUTHOR]

Background Blood lipid concentrations are causally related to the risk of coronary heart disease (CHD). Various associations between CHD risk and genes that moderately affect plasma lipid levels have been described, but previous studies have typically involved too few ‘cases’ to assess these associations reliably.Methods The present study involves 4685 cases of myocardial infarction (MI) and 3460 unrelated controls without diagnosed cardiovascular disease. Six polymorphisms of four ‘lipid-related’ genes were genotyped.Results For the apolipoprotein E ɛ2/ɛ3/ɛ4 polymorphism, the average increase in the plasma ratio of apolipoprotein B to apolipoprotein A1 (apoB/apoA1 ratio) among controls was 0.082 (s.e. 0.007) per stepwise change from ɛ3/ɛ2 to ɛ3/ɛ3 to ɛ3/ɛ4 genotype (trend P < 0.0001). The case-control comparison yielded a risk ratio for MI of 1.16 (95% CI: 1.06, 1.27; P = 0.001) per stepwise change in these genotypes. But, this risk ratio was not as extreme as would have been expected from the corresponding differences in plasma apoB/apoA1 ratio between genotypes. Hence, following adjustment for the measured level of the plasma apoB/apoA1 ratio, the direction of the risk ratio per stepwise change reversed to 0.83 (95% CI: 0.74, 0.92; P < 0.001). Similarly, for the apolipoprotein B Asn4311Ser and Thr71Ile polymorphisms, genotypes associated with more adverse plasma apolipoprotein concentrations were associated with significantly lower risk of MI after adjustment for the apoB/apoA1 ratio. The B2 allele of the cholesteryl ester transfer protein TaqIb polymorphism was associated with a significantly lower plasma apoB/apoA1 ratio, but with no significant difference in the risk of MI. Finally, the lipoprotein lipase Asn291Ser and T4509C (PvuII) polymorphisms did not produce clear effects on either the plasma apoB/apoA1 ratio or the risk of MI.Conclusions It remains unresolved why some of these genetic factors that produce lifelong effects on plasma lipid concentrations have significantly less than the correspondingly expected effects on CHD rates in adult life. [ABSTRACT FROM AUTHOR]

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism and a major candidate gene for coronary heart disease (CHD). The authors assessed associations between 7 LPL polymorphisms and lipid fractions and CHD risk in population-based cohort, case-control, and cross-sectional studies published by January 2007. Meta-analyses of 22,734 CHD cases and 50,177 controls in 89 association studies focused on the relations of the T-93G (rs1800590), D9N (rs1801177), G188E, N291S (rs268), PvuII (rs285), HindIII (rs320), and S447X (rs328) polymorphisms to high density lipoprotein cholesterol, triglycerides, myocardial infarction, or coronary stenosis. Carriers of 9N or 291S had modestly adverse lipid profiles. Carriers of the less common allele of HindIII or of 447X had modestly advantageous profiles. The combined odds ratio for CHD among carriers was 1.33 (95% confidence interval (CI): 1.14, 1.56) for 9N, 1.07 (95% CI: 0.96, 1.20) for 291S, 0.89 (95% CI: 0.81, 0.98) for the less common HindIII allele, and 0.84 (95% CI: 0.75, 0.94) for 447X. For T-93G (odds ratio (OR) = 1.22, 95% CI: 0.98, 1.52) and PvuII (OR = 0.96, 95% CI: 0.89, 1.04), there were null associations with lipid levels or CHD risk; information on G188E was limited (OR = 2.80, 95% CI: 0.88, 8.87). The study of LPL genotypes confirms the existence of close interrelations between high density lipoprotein cholesterol and triglyceride pathways. The influence of these genotypes on CHD risk warrants further investigation. [ABSTRACT FROM AUTHOR]