Adherence to dietary guidelines and risk of dementia: a prospective cohort study of 94 184 individuals.

AIMS: Recent estimates suggest that 40% of dementia cases could be avoided by treating recognised cardiovascular risk factors such as hypertension, diabetes, smoking and physical inactivity. Whether diet is associated with dementia remains largely unknown. We tested if low adherence to established dietary guidelines is associated with elevated lipids and lipoproteins and with increased risk of Alzheimer's disease and non-Alzheimer's dementia ­ a dementia subtype with a high frequency of cardiovascular risk factors. METHODS: We used the prospective Copenhagen General Population Study including 94 184 individuals with dietary information and free of dementia at baseline. Mean age at study entry was 58 years, and 55% (N = 51 720) were women and 45% (N = 42 464) were men. Adherence to dietary guidelines was grouped into low, intermediate and high adherence based on food frequency questionnaires. Main outcomes were non-Alzheimer's dementia and Alzheimer's disease. RESULTS: Low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and plasma triglyceride levels were higher in individuals with intermediate and low adherence to dietary guidelines compared with individuals with high adherence (all p for trends <0.001). Age and sex-adjusted hazard ratios (HRs) for non-Alzheimer's dementia v. individuals with high adherence were 1.19 (95% confidence interval 0.97­1.46) for intermediate adherence, and 1.54 (1.18­2.00) for low adherence. Corresponding HRs in multivariable-adjusted models including APOE genotype were 1.14 (0.92­1.40) and 1.35 (1.03­1.79). These relationships were not observed in individuals on lipid-lowering therapy. CONCLUSIONS: Low adherence to national dietary guidelines is associated with an atherogenic lipid profile and with increased risk of non-Alzheimer's dementia ­ the subtype of dementia with a high frequency of vascular risk factors. This study suggests that implementation of dietary guidelines associated with an anti-atherogenic lipid profile could be important for prevention of non-Alzheimer's dementia.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people.

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case-control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

Aerobic exercise training lowers platelet reactivity and improves platelet sensitivity to prostacyclin in pre- and postmenopausal women.

Essentials It is unknown how regular exercise affects platelet function after menopause. We studied the effect of 3-months of high-intensity exercise in pre- and postmenopausal women. Platelet sensitivity to the inhibitory effect of arterially infused prostacyclin was increased. Reduced basal platelet reactivity was seen in the premenopausal women only. SUMMARY: Background The risk of atherothrombotic events increases after the menopause. Regular physical activity has been shown to reduce platelet reactivity in younger women, but it is unknown how regular exercise affects platelet function after the menopause. Objectives To examine the effects of regular aerobic exercise in late premenopausal and recent postmenopausal women by testing basal platelet reactivity and platelet sensitivity to prostacyclin and nitric oxide. Methods Twenty-five sedentary, but healthy, late premenopausal and 24 matched recently postmenopausal women, mean (95% confidence interval) 49.1 (48.2-49.9) and 53.7 (52.5-55.0) years old, participated in an intervention study: 3-month high-intensity supervised aerobic spinning-cycle training (1 h, × 3/week). Basal platelet reactivity was analyzed in platelet-rich plasma from venous blood as agonist-induced % aggregation. In a subgroup of 13 premenopausal and 14 postmenopausal women, platelet reactivity was tested ex vivo after femoral arterial infusion of prostacyclin, acetylcholine, a cyclooxygenase inhibitor, and after acute one-leg knee extensor exercise. Results Basal platelet reactivity (%aggregation) to TRAP-6 (1 µm) was higher in the postmenopausal, 59% (50-68), than the premenopausal women, 45% (35-55). Exercise training reduced basal platelet reactivity to collagen (1 µg mL-1 ) in the premenopausal women only: from 63% (55-71%) to 51% (41-62%). After the training intervention, platelet aggregation was more inhibited by the arterial prostacyclin infusion and the acute exercise in both premenopausal and postmenopausal women. Conclusions These results highlight previously unknown cardioprotective aspects of regular aerobic exercise in premenopausal and postmenopausal women, improving their regulation of platelet reactivity through an increased platelet sensitivity to prostacyclin, which may counterbalance the increased atherothrombotic risk associated with the menopause.

Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis.

BACKGROUND: Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear. OBJECTIVE: We tested the hypothesis that elevated plasma bilirubin is causally related to decreased risk of IHD and MI. DESIGN: We used a Mendelian randomization approach and three independent studies from Copenhagen, Denmark. We measured bilirubin in 43 708 white individuals from the general population, and genotyped rs6742078 G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in 67 068 individuals, of whom 11 686 had IHD. RESULTS: Third versus first tertile of baseline bilirubin levels was associated with 134% increased bilirubin levels, with sex- and age-adjusted hazard ratios (HRs) of 0.86 [95% confidence interval (CI), 0.76-0.98; P = 0.02] for IHD and 0.81 (95% CI, 0.66-0.99; P = 0.04) for MI, but with corresponding multifactorially adjusted HRs of 0.93 (95% CI, 0.82-1.06; P = 0.29) and 0.90 (95% CI, 0.73-1.12; P = 0.35). UGT1A1 rs6742078 TT versus GG genotype was associated with 95% increased bilirubin levels (P < 0.001); TT versus GG genotype was associated with odds ratios (ORs) of 1.03 (95% CI, 0.96-1.11; P = 0.73) for IHD and 1.01 (95% CI, 0.92-1.12; P = 0.68) for MI. Finally, in a meta-analysis of the present three studies and eight previous studies including a total of 14 711 cases and 60 324 controls, the random effects OR for ischaemic cardiovascular disease for genotypes with approximately 100% increased bilirubin levels versus reference genotypes was 1.01 (95% CI, 0.88-1.16). CONCLUSION: These data suggest that plasma bilirubin is not causally associated with risk of IHD.

Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels.

OBJECTIVES: To determine whether mutations in APOA1 affect levels of high-density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population. BACKGROUND: Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A-I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death. DESIGN: We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case-control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA-I in human heterozygotes and functional effects of mutations in adenovirus-transfected mice. RESULTS: We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 [95% confidence interval (CI): 1.6-6.5], 5.5 (95% CI: 2.6-11.7) and 2.5 (95% CI: 1.3-4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case-control study. Furthermore, the ratio of mutant S164 to WT A164 apoA-I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA-I, and this finding was confirmed in adenovirus-transfected mice. CONCLUSIONS: A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.

Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population.

Glutathione-S-transferase T1 (GSTT1) and GSTM1 detoxify carcinogens and thus potentially contribute to inter-individual susceptibility to cancer. We determined the ability of GST copy number variation (CNV) to predict the risk of cancer in the general population. Exact copy numbers of GSTT1 and GSTM1 were measured by real-time PCR in 10 247 individuals, of whom 2090 had cancer. In men, the cumulative incidence of prostate cancer increased and the cumulative 5-year survival decreased with decreasing GSTT1 copy numbers (trends=0.02). The hazard ratios (HRs) (95% CIs) for prostate cancer and for death after prostate cancer diagnosis were, respectively, 1.2 (0.8-1.8) and 1.2 (0.6-2.1) for GSTT1*1/0, and 1.8 (1.1-3.0) and 2.2 (1.1-4.4) for GSTT1*0/0 versus GSTT1*1/1. In women, the cumulative incidence of corpus uteri cancer increased with decreasing GSTT1 copy numbers (trend=0.04). The HRs for corpus uteri cancer were, respectively, 1.8 (1.0-3.2) and 2.2 (1.0-4.6) for GSTT1*1/0 and GSTT1*0/0 versus GSTT1*1/1. Finally, the cumulative incidence of bladder cancer increased, and the cumulative 5-year survival decreased, with decreasing GSTM1 copy numbers (P=0.03-0.05). The HRs for bladder cancer were, respectively, 1.5 (0.7-3.2) and 2.0 (0.9-4.3) for GSTM1*1/0 and GSTM1*0/0 versus GSTM1*1/1. The HR for death after bladder cancer diagnosis was 1.9 (1.0-3.7) for GSTM1*0/0 versus GSTM1*1/0. In conclusion, exact CNV in GSTT1 and GSTM1 predict incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer.

The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases.

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

Variation in 5' promoter region of the APOE gene contributes to predicting ischemic heart disease (IHD) in the population at large: the Copenhagen City Heart Study.

The objective of this study was to evaluate whether an increased hazard of developing ischemic heart disease (IHD) is associated with any of the three genotypes A560T832/A560T832, A560T832/A560G832 and A560T832/T560T832, defined by variations in two non-coding SNPs in the 5' promoter region of the apolipoprotein E (APOE) gene. These genotypes were selected because they distinguished between high and low levels of HDL-C, TG and/or T-C in our earlier study of multiple samples defined by gender and population. We found a significant increase (p<0.05) in the hazard of IHD in females with the A560T832/T560T832 genotype that remained significant after fitting the effects of dyslipidemia, other established risk factors, and the structural isoform variations of the ApoE molecule. We discuss why this statistically significant genetic predictor may not be an appropriate screening test for IHD in the Danish population at large.

APOE genotype predicts AD and other dementia but not ischemic cerebrovascular disease.

BACKGROUND: The APOE polymorphism is an important modulator of plasma lipoproteins and a risk factor for AD. The hypothesis that APOE genotype, through its effect on lipoproteins, is a common risk factor for ischemic cerebrovascular disease (ICVD), AD, and other dementia (OD) was tested. METHODS: The authors genotyped 9241 individuals from the general population, 452 patients with ICVD and > or = 50% stenosis of the carotid arteries, and 75 patients with ICVD before the age of 50 years. Among the individuals from the general population, 211 had ICVD, 26 had AD, and 28 had OD. RESULTS: The APOE polymorphism was not associated with ICVD in any of the three patient groups. In contrast, the epsilon43 and epsilon44 genotypes were associated with 3- and 10-fold risks of AD (95% CI = 1.4 to 8.0 and 2.5 to 41.0), and the epsilon43 genotype was also associated with a 2.5-fold risk of OD (95% CI = 1.1 to 5.5). These increases in risk were not abolished by adjustment for lipids and lipoproteins. The fraction of AD that could be attributed to the epsilon43 and epsilon44 genotypes was 37 and 20% in the general population, whereas the fraction of OD that could be attributed to the epsilon43 genotype was 26%. CONCLUSION: The APOE polymorphism is a risk factor for AD and OD independent of lipid and lipoprotein levels but does not affect the risk of ICVD.

Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype.

Variation in apolipoprotein (apo)E genotypes predicts variation in plasma cholesterol and apoB; however, the context-dependent associations between high density lipoprotein (HDL) cholesterol, apoA-I, triglycerides, and lipoprotein[a] (Lp[a]) and this polymorphism remain unsettled. We genotyped 5,025 women and 4,035 men sampled to represent a white general population in the age range 20 to 80+ years (mean ages 58 and 57 years for women and men, respectively). The relative frequencies of the varepsilon22, varepsilon32, varepsilon42, varepsilon33, varepsilon43, and varepsilon44 genotypes were 0.005, 0.127, 0.027, 0.564, 0.251, and 0. 027, respectively. Variations in apoE genotype (in the order listed above) predicted stepwise increases in cholesterol and apoB in both genders (all ANOVAs: P < 0.001), and stepwise decreases in HDL cholesterol and apoA-I in women (both ANOVAs: P < 0.001), but not in men. In both genders varepsilon33 individuals had the lowest levels of nonfasting triglycerides, whereas the highest levels were found in individuals with varepsilon22 and varepsilon44 genotypes (both ANOVAs: P < 0.001). Finally, a stepwise increase in Lp[a] was seen in women (ANOVA: P < 0.001), but not in men. In women, the association between variation in nonfasting triglycerides and Lp[a], and variation in apoE genotypes was mainly seen in those with the highest alcohol consumption, similar to the consumption of most men. Variations in apoE genotype predicted 5% and 11% in women, and 2% and 6% in men, of the total variation in plasma cholesterol and apoB, respectively. Variation in levels of plasma lipoproteins is associated with variation in apoE genotypes in the population at large, with the most pronounced association in women, except for nonfasting triglycerides, for which the association is most pronounced in men.Whereas the associations between variation in plasma cholesterol and apoB and the variation in apoE genotypes seem invariant, the associations with variation in plasma HDL cholesterol, apoA-I, nonfasting triglycerides, and Lp[a] seem context dependent.

Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study.

OBJECTIVES: We tested the hypothesis that risk of ischemic heart disease (IHD) differs as a function of apolipoprotein E (APOE) genotype in women and men. BACKGROUND: Apolipoprotein E genotype influences lipids and lipoproteins and, therefore, possibly the risk of IHD. METHODS: We genotyped 9,241 white women and men from the general population and 940 white women and men with IHD. RESULTS: Test of interaction suggested that APOE genotype may influence risk of IHD differently in women and men (p = 0.07). After age adjustment, the odds ratio (OR) for IHD for epsilon32 versus epsilon33 women was 0.57 (95% confidence interval [CI]: 0.35 to 0.94) while epsilon43 and epsilon44 versus epsilon33 men had ORs of 1.16 (0.96 to 1.41) and 1.58 (1.01 to 2.45). After adjustment for age and other conventional cardiovascular risk factors, the equivalent ORs were for epsilon32 women 0.38 (0.18 to 0.79), for epsilon43 men 1.35 (1.02-1.78) and for epsilon44 men 1.58 (0.80 to 3.08). Equivalent ORs for epsilon43 and epsilon44 versus epsilon33 women and for epsilon32 versus epsilon33 men were all close to 1.0 and nonsignificant. Of the total risk of IHD relative to the epsilon33 genotype, the fraction attributed to epsilon32 in women was -9%, while the fractions attributed to epsilon43 and epsilon44 in men were +8% and +2%. CONCLUSIONS: Relative to epsilon33 individuals, epsilon32 women are protected while epsilon43 and epsilon44 men are particularly susceptible to IHD.

Context-dependent and invariant associations between APOE genotype and levels of lipoproteins and risk of ischemic heart disease: a review.

Apolipoprotein E (APOE) plays a pivotal role in the catabolism of triglyceride-rich lipoproteins by serving as a ligand for lipoprotein receptors. The common three-allele (epsilon 2/epsilon 3/epsilon 4) variation in the APOE gene is the most studied susceptibility polymorphism to date, identified in more than 50 different populations worldwide. Differences in the associations between APOE genotype and lipids, lipoproteins, and risk of ischemic heart disease between and within studies have raised the possibility that this gene is expressed in a context-dependent rather than invariant manner. The objective of this review was to focus on studies that in particular yield information about such context-dependent associations of the APOE polymorphism. The well-documented pattern of increasing cholesterol levels from epsilon 2 to epsilon 3 to epsilon 4 seems invariant across different populations; however, the magnitude of this association appears to be modifiable by gender, exogenous estrogens, diet and perhaps by body size. The less pronounced associations between the APOE polymorphism and high-density lipoprotein (HDL) cholesterol and triglycerides appear to differ by gender, to be enhanced by hyperglycemia and alcohol consumption, and abolished by exogenous estrogens in women, thus suggesting strong context dependency. The APOE polymorphism explains more of the variation in levels of cholesterol and apolipoprotein B (APOB) in women than in men, whereas a larger fraction of the variation in triglycerides is explained by the APOE polymorphism in men than in women. Finally, relative to epsilon 33 individuals, epsilon 32 women may be protected while epsilon 43 and epsilon 44 men may be particularly susceptible to ischemic heart disease. In conclusion, differences in magnitude or presence of APOE gene associations across studies or across subgroups within studies appear to be due to the influence of gender, exogenous estrogens, diet, hyperglycemia, alcohol consumption and perhaps body size. Consequently, these contexts should be considered when APOE polymorphism is studied.

Apolipoprotein E genotypes predict attendance rates at lipid clinic.

Except for the rare epsilon22 genotype it remains largely unsettled whether apolipoprotein E genotype influences an individual's referral to lipid clinics. To test this hypothesis, we compared genotype distributions among 156 hypercholesterolemic and 83 hypertriglyceridemic patients attending a lipid clinic with that among 9241 individuals sampled from the Danish general population. The relative genotype frequencies of epsilon22, epsilon32, epsilon42, epsilon33, epsilon43, and epsilon44 were 0.005, 0.126, 0.026, 0.564, 0.251, and 0.027 in the general population, which differed from genotype frequencies in both hypercholesterolemic (chi2: P = 0.01) and hypertriglyceridemic patients (chi2: P < 0.001). By comparison with epsilon33, epsilon44 predicted a 2-fold increase whereas epsilon32 predicted a 2-fold decrease in the attendance rate at the lipid clinic for hypercholesterolemic patients (95% confidence intervals: 1.1-4.3 and 0.2-0.9). Among hypertriglyceridemic patients, epsilon22, epsilon42, epsilon43, and epsilon44 versus epsilon33 predicted 13-, 3-, 1 1/2-, and 3-fold attendance rates at the lipid clinic, respectively (95% confidence intervals: 4.5-39.9, 1.2-8.4, 1.0-2.8, and 1.1-7.6). These findings are in accordance with the fact that epsilon44 raises cholesterol levels, epsilon32 reduces cholesterol levels, and epsilon22, epsilon42, epsilon43, and epsilon44 raise triglyceride levels in comparison with epsilon33. These data suggest that hypercholesterolemic individuals carrying epsilon44 and hypertriglyceridemic individuals carrying epsilon22, epsilon42, epsilon43, or epsilon44 are relatively more often referred to lipid clinics than carriers of epsilon33.

LDL receptor mutations and ApoB mutations are not risk factors for ischemic cerebrovascular disease of the young, but lipids and lipoproteins are.

BACKGROUND: The genetic background for ischemic cerebrovascular disease of the young and the role of lipids and lipoproteins as risk factors are not clear. METHODS: We determined five LDL receptor mutations (Trp23Stop, Trp66Gly, Trp556Ser, 313+1G --> A, 1846-1G --> A) and three apolipoprotein B mutations (Arg3500Gln, Arg3500Trp, Arg3531Cys), and other risk factors for ischemic cerebrovascular disease in 80 patients (36 women, 44 men) with onset of disease before the age of 50 years compared with 3366 individuals from a general population sample within the same age range. RESULTS: None of the patients were carriers of mutations in the LDL receptor (Trp23Stop, Trp66Gly, Trp556Ser, 313+1G --> A, 1846 - 1G --> A) or the apolipoprotein B gene (Arg3500Gln, Arg3500Trp, Arg3531Cys) associated with hypercholesterolemia. However, on univariate analysis as well as on logistic regression analysis allowing for age and gender, plasma cholesterol (OR 1.4; P < 0.0005), HDL-cholesterol (OR 0.4; P < 0.005), diabetes (OR 5.8; P < 0.0001), and hypertension (OR 3.9; P < 0.001) were significant predictors of ischemic cerebrovascular disease. CONCLUSIONS: The five most common LDL receptor mutations in Danish patients with familial hypercholesterolemia and three mutations in the apolipoprotein B gene did not predispose to ischemic cerebrovascular disease of the young. However, cholesterol and HDL-cholesterol are important risk factors for ischemic cerebrovascular disease of the young in the present study. The elevation in cholesterol could in some patients be due to rare LDL receptor mutations not tested for, and could in other patients be multifactorial in origin.

ACE gene polymorphism as a risk factor for ischemic cerebrovascular disease.

BACKGROUND: Researchers have suggested that the deletional allele of the ACE (angiotensin-converting enzyme) gene insertion-deletion polymorphism is a potent risk factor for myocardial infarction. This association could not be confirmed in the Copenhagen City Heart Study, in which 10,150 persons were studied. The ACE gene polymorphism has also recently been suggested as a potent risk factor for ischemic cerebrovascular disease. OBJECTIVE: To investigate the association between ACE gene polymorphism and ischemic cerebrovascular disease. DESIGN: Two case-referent studies and a cross-sectional study. SETTING: University hospital in Copenhagen, Denmark. PARTICIPANTS: Case-referent study 1: 35 women and 38 men who developed ischemic cerebrovascular disease before 50 years of age compared with 1454 women and 1737 men from a general population sample. Case-referent study 2: 82 women and 137 men with ischemic cerebrovascular disease and carotid stenosis greater than 40% compared with 4273 women and 3091 men from the general population sample. Cross-sectional study of the general population sample: 67 women and 93 men with ischemic cerebrovascular disease compared with 4077 women and 3156 men without such disease. MEASUREMENTS: Genotype; age; body mass index; smoking habits; levels of lipids, lipoproteins, apolipoproteins, and fibrinogen; and diagnosis of hypertension, diabetes mellitus, and ischemic cerebrovascular disease. RESULTS: Odds ratios for ischemic cerebrovascular disease by ACE genotype classes were not significantly different from 1.0 in women or men in any of the three studies, separately or combined. In a logistic regression analysis that controlled for age and conventional cardiovascular risk factors, odds ratios in either sex still did not significantly differ from 1.0 in any study, separately or combined. CONCLUSION: In two case-referent studies, a cross-sectional study, and the three studies combined, no statistically significant difference was found in the development of ischemic cerebrovascular disease between genotype classes of the ACE gene polymorphism in women or men.