Risk Of Ischemic Cerebrovascular Disease Research Articles

Prevalence, Awareness, and Control of Hypertension among Diabetic Koreans

Prevalence, Awareness, and Control of Hypertension among Diabetic Koreans

CYP1B1 genotype and risk of cardiovascular disease, pulmonary disease, and cancer in 50 000 individuals

Cytochrome P450 (CYP) 1B1 enzymes metabolize tobacco-smoke polycyclic aromatic hydrocarbons and 17beta-estradiol. CYP1B1*3 (rs1056836 = Leu432Val = 4326C>G) and CYP1B1*4 (rs1800440 = Asn453Ser = 4390A>G) influence this metabolism. We, therefore, hypothesized that these two polymorphisms associate with risk of myocardial infarction (MI), ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), chronic obstructive pulmonary disease (COPD), cancer overall, tobacco-related cancer, and female cancer, possibly dependent on tobacco exposure. We genotyped 10 391 adults from the Copenhagen City Heart Study, who had been followed prospectively for more than 30 years. Significant results were retested cross-sectionally in the Copenhagen General Population Study (CGPS) with 37 178 participants, and in the Copenhagen Ischemic Heart Disease Study with 2379 cases and 33 220 controls. In the Copenhagen City Heart Study, hazard ratio for MI among never smokers was 1.9 (95% confidence interval: 1.2-3.2) for CYP1B1*3 GG (19%) versus CC (32%). These findings were, however, not confirmed when retested in CGPS and Copenhagen Ischemic Heart Disease Study. For tobacco-related cancer, we found decreasing risk with CYP1B1*3 CG and GG versus CC; however, this could not be confirmed in the CGPS. For IHD, ICVD, COPD, cancer overall, and female cancer, we found no association with CYP1B1*3 genotype, overall or according to smoking status. For CYP1B1*4 genotype, we did not find any association with either endpoint, overall or according to smoking status. CYP1B1*3 and CYP1B1*4 genotypes did not associate with the risk of MI, IHD, ICVD, COPD, cancer overall, tobacco-related cancer, or female cancer.

Prothrombin and risk of venous thromboembolism, ischemic heart disease and ischemic cerebrovascular disease in the general population

ObjectiveWe tested the hypotheses that Prothrombin G20210A heterozygosity associate with increased risk of venous thromboembolism (VTE), ischemic heart disease (IHD), and ischemic cerebrovascular disease (ICVD) in the general population and re-tested risk of IHD and ICVD in two case-control studies. Methods9231 individuals from the Danish general population were followed for VTE (VTE=DVT+PE), deep venous thrombosis (DVT), pulmonary embolism (PE), IHD, myocardial infarction (MI), ICVD, and ischemic stroke (IS) for a median of 24 years. Case-control studies included 2461 IHD cases and 867 ICVD cases. ResultsIn the general population, Prothrombin G20210A heterozygotes had1.3 (95% CI:0.6–2.9) fold risk for VTE, 0.6 (0.2–2.0) for DVT, 1.7(0.6–4.8) for PE, 1.5(1.1–2.1) for IHD, 1.7(1.1–2.7) for MI, 1.1(0.6–1.9) for ICVD, and 1.1(0.5–2.1) for IS compared to non-carriers. Double heterozygotes for Prothrombin G20210A and Factor V Leiden versus double non-carriers had a multifactorially adjusted hazard ratio for IHD of 6.0(2.0–19). In case-control studies, multifactorially adjusted odds ratios for Prothrombin G20210A heterozygotes versus non-carriers were 2.0(1.1–3.4) for IHD, 2.0(1.0–3.8) for MI, 1.4(0.7–3.1) for ICVD, and 2.1(0.8–5.4) for IS. ConclusionProthrombin G20210A heterozygosity alone and in combination with Factor V Leiden R506Q heterozygosity predicts 1.5 and 6.0 fold risk of IHD compared to non-carriers.

Lipoprotein lipase genetic variation and gender-specific ischemic cerebrovascular disease risk.

The lipoprotein lipase gene is highly polymorphic, and several common mutations have been associated with an increased atherogenic lipid profile. One of these, Asn291Ser, was also found to be associated with increased ischemic heart disease in women. More recently, this same mutation, present in approximately 5% of the population, was also associated with increased ischemic cerebrovascular disease risk. The magnitude of this increase is less than or equal to that attributed to other modifiable risk factors, such as hypertension, smoking, and hypercholesterolemia. A prudent diet and lifestyle should therefore attenuate the higher genetic predisposition to atherosclerosis observed in women carrying this mutation.

Cysteinyl-Leukotrienes in Cerebrovascular Disease

Although the initial interest in the field of leukotriene (LT) research was focused on their potent bronchoconstrictive effects, subsequent studies have suggested LTs as key mediators in several inflammatory diseases. Genetic variations within the enzymes transforming arachidonic acid into LTs (Figure) have for example been associated with atherosclerosis and an increased risk of cardiovascular events.1 Figure Metabolism of arachidonic acid into leukotrienes (LTs) by 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP), LTA4 hydrolase (LTA4H), and LTC4 synthase (LTC4S). Cysteinyl-LTs (LTC4, LTD4, LTE4) activate CysLT receptors, which can be targeted by antiasthmatic CysLT1 receptor antagonists. Inset shows the 5 exons (I-V) of the LTC4S gene and its 5′-flanking untranscribed region (UTR). The 2 reported single nucleotide polymorphisms (SNP) are located at 444 and 1072 bp upstream, respectively. The −444 A to C substitution has been associated with increased LTC4 synthesis in eosinophils,6 aspirin intolerant asthma,5 increased risk for coronary calcium,10 increased carotid artery intima media thickness (IMT),10 and a decreased risk of ischemic cerebrovascular events.4 See accompanying article on page 990 Leukotriene C4 synthase (LTC4S; Figure) is a microsomal glutathione-S-transferase (mGST), which conjugates LTA4 with glutathione.2 The product, LTC4, shares its following enzymatic steps with glutathione to …

Promotor Polymorphisms in Leukotriene C 4 Synthase and Risk of Ischemic Cerebrovascular Disease

Cysteinyl leukotrienes are involved in inflammation and possibly in early carotid atherosclerosis. We tested the hypothesis that the -444 A/C and -1072 G/A polymorphisms of the leukotriene C(4) synthase associate with risk of ischemic cerebrovascular disease. We genotyped 10 592 individuals from the Danish general population, the Copenhagen City Heart Study. During 24 years of follow-up, 557 individuals developed ischemic cerebrovascular disease. The allele frequency was 0.07 for -1072 A and 0.29 for -444 C. Cumulative incidence for ischemic cerebrovascular disease was higher for -1072 AA versus GG genotype (log-rank: P=0.002), and lower for -444 CC versus AA genotype (log-rank: P=0.008). Combined genotypes showed corresponding cumulative incidence differences (log-rank: P=0.003). Multifactorially adjusted hazard ratios for ischemic cerebrovascular disease were 2.8(1.4 to 5.7) for -1072 AA versus GG genotype, 0.6(0.4 to 0.9) for -444 CC versus AA genotype, 2.5(1.2 to 5.4) for combined AA-AA versus GG-AA genotype, and 0.6(0.4 to 0.9) for combined GG-CC versus GG-AA genotype. Genotype did not associate with risk of deep venous thrombosis or severe carotid atherosclerosis, or with levels of platelets and coagulation factors. Leukotriene C(4) synthase -1072 AA genotype predict increased risk, whereas -444 CC genotype predict decreased risk of ischemic cerebrovascular disease.

PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden

Genetic variants in Phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland. We investigated whether these variants associate with ICVD in Sweden. Previously published PDE4D and ALOX5AP gene variants were genotyped for cases (685) and controls (751). In PDE4D this consisted of SNP41, SNP45 and microsatellite AC008818-1 and in ALOX5AP four SNPs that define the HapA haplotype. The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype (SNP45: RR=1.43, P=0.063, SNP41: RR=1.57, P=0.018). The SNP haplotype GA (SNP45, SNP41) showed an increased risk for LAA (RR=1.58, P=0.016) and the combined LAA and Cardioembolism (CE) (RR=1.34, P=0.031) subgroups. As the SNPs are in strong LD, this haplotype corresponds to the complement of the protective haplotype in the Icelandic study. No allele of the microsatellite marker, showed association to stroke or any subtype and nor did the Icelandic PDE4D at-risk haplotype (GA0). We did not confirm the association between ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the LAA subtype. Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, are consistent with the association observed in the original study, with a trend observed in the whole ICVD group, which was strengthened in the stroke subtype LAA and the combined group of LAA and CE stroke. This supports the notion that PDE4D contributes to the risk of developing stroke.

Polymorphisms in Apolipoprotein B and Risk of Ischemic Stroke

Apolipoprotein B levels associate with risk of ischemic stroke. APOB polymorphisms may influence levels of apolipoprotein B and low-density lipoprotein (LDL), but whether they associate with risk of ischemic stroke is unknown. We tested the hypothesis that the APOB T71I, A591V, P2712L, R3611Q, E4154K, and N4311S polymorphisms associate with risk of ischemic stroke in the general population and performed in vivo human LDL turnover studies of E4154K heterozygotes vs. K4154K homozygotes. This was a prospective study (the Copenhagen City Heart Study) with 23-yr, 100% complete follow-up. The study was conducted with a Danish general population. A total of 9157 women and men aged 20-80+ yr participated in the study. Risk of ischemic cerebrovascular disease and ischemic stroke, apolipoprotein B and LDL levels, and LDL fractional catabolic rate were measured. The hypothesis was formulated before genotyping. APOB K4154K homozygotes had an age-adjusted hazard ratio of 0.4 (95% confidence interval 0.2-0.9) for ischemic cerebrovascular disease and 0.2 (0.1-0.7) for ischemic stroke relative to E4154E homozygotes. Corresponding multifactorially adjusted hazard ratios were 0.5 (0.2-1.0) and 0.2 (0.1-0.8). Furthermore, E4154K heterozygotes and K4154K homozygotes had lower levels of apolipoprotein B and LDL cholesterol, compared with E4154E homozygotes. Finally, E4154K heterozygotes had an increased fractional catabolic rate of LDL relative to E4154E homozygotes. None of the other polymorphisms studied influenced risk of ischemic stroke. APOB K4154K homozygosity predicts a 3- to 5-fold reduction in risk of ischemic cerebrovascular disease and ischemic stroke. This may be explained by lower plasma levels of apolipoprotein B and LDL cholesterol caused by an increased catabolism of LDL particles, although another yet-unknown mechanism is also possible.

Hereditary hemochromatosis genotypes and risk of ischemic stroke

We tested the hypothesis that the HFE genotypes H63D/H63D, H63D/wild type, C282Y/H63D, C282Y/C282Y, and C282Y/wild type are risk factors for symptomatic carotid atherosclerosis, ischemic cerebrovascular disease (ICVD), and ischemic stroke. We performed an age- and gender-matched case-control study of 701 cases with symptomatic carotid atherosclerosis vs 2,777 controls, and a prospective study of 9,178 individuals from the Danish general population followed for 24 years, during which 504 developed ICVD, of whom 393 had ischemic stroke. Genotype was not consistently associated with symptomatic carotid atherosclerosis. The cumulative incidences of ICVD and ischemic stroke by age were increased for H63D/H63D vs wild type/wild type (log-rank: p = 0.003 and p < 0.001). H63D/H63D vs wild type/wild type had an age- and multifactorially adjusted hazard ratio of 2.0 (95% CI: 1.2 to 3.2; p = 0.007) and 2.1 (1.3 to 3.5; p = 0.004) for ICVD and of 2.4 (1.4 to 4.0; p = 0.001) and 2.8 (1.7 to 4.6; p < 0.001) for ischemic stroke; these remained significant after correction for multiple comparisons. Other hereditary hemochromatosis genotypes were not associated with ICVD or ischemic stroke. Hereditary hemochromatosis H63D homozygosity predicts a two- to threefold risk of ICVD and ischemic stroke.

Association among apolipoprotein E gene polymorphism, diabetes mellitus, and ischemic cerebrovascular disease in Koreans

The association between apolipoprotein E (apoE) gene polymorphism and ischemic cerebrovascular disease (ICVD) has been controversial. These controversies may be due to inaccurate classification of patients and ethnic differences. The aim of the present study was to assess the relationship between apoE gene polymorphism and the development of ICVD in a population from Korea. We investigated 136 patients with ICVD and 357 controls without ICVD. No differences in the apoE genotypes frequencies (<TEX>$X^{2}$</TEX> = 3.660, df = 5, P = 0.454) and even in the alleles frequencies (<TEX>$X^{2}$</TEX> = 1.946, df = 2, P = 0.378) were observed in the ICVD patients compared with that in controls. The data have been compared with data found in other population groups. However, the risk of ICVD associated with apoE <TEX>${\varepsilon}3/{\varepsilon}4$</TEX> genotype was increased nearly 3-fold in subjects possessing the history of diabetes mellitus (OR 3.3, 95% CI 1.2-9.4, P = 0.026). We concluded that the apoE polymorphism is not associated with ICVD at least in the Korean population, but the apoE frequencies found in this study differ significantly from those obtained in Japanese.

IL6 -174 G/C and Fibrinogen-β-455 G/A Polymorphisms in Ischemic Cerebrovascular Disease (ICD).

Ischemic cerebrovascular disease (ICD) is a multi-factorial entity whose anatomopathologic substrate is atherosclerosis. The inflammatory cells migrate to vascular endothelium and release chemokines such as interleukin 6 (IL6), resulting in the atheroma plaque development. The IL6 production induces acute phase proteins synthesis such as fibrinogen.Objective. The purpose of this case-control study is to analyze the ICD risk associated to the polymorphisms IL6-174 G/C and beta chain of fibrinogen-455 G/A (fibri-β-455). The association of these polymorphisms, classic vascular risks factors and ICD subtypes according to TOAST classification has also been explored.Methods and patients. A total of 159 ICD diagnosed patients (82 female and 77 male; mean age 67.7±15) were analysed. They were matched for age (±5 years) and sex with a control group (65.6±14) without thrombotic history. AHT, DM, dyslipidaemia and smoking habit data were collected for each group. Polymorphisms were analysed by PCR-RFLP. Serum IL6 was measured by ELISA and fibrinogen by Clauss method. Statistic analysis was made with the SAS v9 software.Results. Genotype analysis showed a significant higher prevalence of the genotypes G/G and G/C IL6 -174 in the patients (OR: 1.49, IC 95%: 0.95–2.34, p: 0.049). By contrast, the fibri-β-455 genotypes were not different in patients and controls (p= 0.230). When the stroke subtypes were analysed, we found that IL6-174 G/C genotype was more frequent in cardioembolic (60.0%) and atherothrombotic ICD subtypes (58.3%). In relation to fibri-β-455 G/A, the A allele showed a increased prevalence in atherothrombotic stroke (43.2%) (p= 0.049).We observed an association between the dyslipidaemia and IL6-174 G/C polymorphism (p= 0.034) and smoking habit with fibri-β-455G/A (p= 0.072). No synergic relation were found between IL6-174 G/C and fibri-β-455 G/A. The G allele IL6-174 G/C carriers group presented higher serum IL6 levels than C allele carriers, 5.85 pg/ml (2.9–34.5) vs. 4.94pg/ml (2.5–11.4). Also, allele A fibri-β-455 G/A was associated with a higher fibrinogen levels than G allele, 329 mg/dl (210–686) versus 280 mg/dl (107–783).Conclusion. There is an association between-174 IL6 G/C polymorphism and ischemic stroke. By contrast, we did not find any association between fibri-β-455 G/A, and ICD. Besides, the analysis performed by ICD subtypes showed an association of this polymorphism and atherothrombotic subtype. These results suggest a relation between smoking habit and fibri-β-455 G/A, and dislypidaemia and-174 IL6 G/C polymorphism.

GLUTATHIONE S-TRANSFERASE GENE POLYMORPHISM AND ISCHEMIC CEREBROVASCULAR DISEASE

Glutathione S-transferase polymorphisms (GST) were examined in 142 cases with ischemic cerebrovascular disease (ICVD) to explore whether the GST polymorphisms confer a risk to an individual to develop ICVD. Tobacco smoke is a major cause of both cancer and vascular disease. The subjects were therefore stratified with ICVD for smoking status, and then the authors examined whether polymorphisms in this detoxification enzyme gene, GST, influence risk of ICVD. The GST genotype was analyzed by the polymerase chain reaction. Neither GSTM1 nor GSTT1 genotypes in the ICVD group was significantly different from the control group (n = 344), even in smokers. The authors attempted the combined analysis for GSTM1 and GSTT1 genotypes in ICVD for smoking status. No significant association was observed among the combined genotypes and ICVD. The observations do not confirm the effect of the GSTM1 and GSTT1 genotypes as a risk factor for ICVD, even in smokers. However, this approach provides a way of addressing the hypothesis that environmental genotoxins could play a role in the etiopathogenesis of ICVD.

White blood cell count and the incidence of ischemic stroke in coronary heart disease patients

Purpose White blood cell (WBC) count is a marker of inflammation and has been associated with the development of cardiovascular disease. We investigated the relationship between WBC counts and the incidence of ischemic cerebrovascular disease in a large cohort of patients with pre-existing atherothrombotic disease and defined blood lipid boundaries. Subjects and methods We followed up patients with documented coronary heart disease for 4.8 to 8.1 years. An extensive medical evaluation, conducted at baseline, included assessment of vascular risk factors and measures of blood lipids. Among 5435 patients with WBC counts, free of stroke, 295 developed an ischemic cerebrovascular disease (fatal and nonfatal). After review of available medical records, 186 of these cases had ischemic stroke or TIA. Results Higher WBC counts were associated with increased risk for ischemic cerebrovascular disease. Age-adjusted hazard ratio (HR) was 1.55 with 95% confidence interval (CI) 1.16-2.07, upper WBC tertile compared with the lowest. Adjusting for clinical covariates, WBC count remained an independent predictor for ischemic cerebrovascular disease (HR = 1.39; 95% CI 1.03-1.87, upper WBC tertile compared with the lowest). A similar trend appeared for the endpoint of ischemic stroke/transient ischemic attack (TIA). Further adjustment for plasma fibrinogen did not change the association materially (HR = 1.32; 95% CI 1.01-1.80; upper tertile of WBC compared with lowest). Conclusions These findings support the role of WBC count as a simple inexpensive and readily available marker for risk stratification of ischemic cerebrovascular disease among patients with pre-existing atherothrombotic disease and defined blood lipid boundaries.

Polymorphism inAPOBAssociated with Increased Low-Density Lipoprotein Levels in Both Genders in the General Population

Rare mutations in APOB cause hypercholesterolemia. Whether common polymorphisms in APOB have similar effects remains controversial. We tested the hypothesis that the APOB 7673C>T polymorphism (T2488T) is associated with variation in low-density lipoprotein (LDL) levels and with risk of ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and total mortality in the general population. The design was a cohort study with 22-yr follow-up (166,232 person years) and two case-control studies, The Copenhagen City Heart Study. The study was performed within the Danish general population and at a university hospital. The study was comprised of 9185 individuals from the general population, 2157 patients with IHD, and 378 patients with ICVD. The main outcome measures were lipids, lipoproteins, apolipoproteins (apo), IHD, ICVD, and total mortality. Genotype was associated with increases in total cholesterol (women/men), LDL cholesterol, and apoB of 0.20/0.26 mmol/liter (3.3%/4.4%), 0.22/0.28 mmol/liter (5.9%/7.8%), and 5.0/5.6 mg/dl (5.9%/6.7%) in TT vs. CC homozygotes, respectively. These results were consistent over time. Despite this, the 7673C>T polymorphism was not associated with risk of IHD, ICVD, or total mortality prospectively or in case-control studies. The APOB 7673C>T polymorphism is associated with moderate increases in total cholesterol, LDL cholesterol, and apoB in both genders in the general population, but not with risk of IHD, ICVD, or total mortality.

Genetic susceptibility to ischemic cerebrovascular disease in Koreans.

Ischemic cerebrovascular disease (ICVD) is a multifactorial disease caused by the interactions of several genetic and environmental factors. Tobacco smoke is a major cause of both cancer and vascular disease. Although its carcinogenic role via induction of DNA damage and mutation is well established, the mechanisms involved in vascular disease remain unclear. One possibility is that DNA damage causes smooth muscle cell proliferation in the intima of arteries, thereby contributing to atherothrombotic processes. The binding of chemicals to DNAis modulated by detoxification enzymes, including glutathione S-transferase (GST). We examined whether polymorphisms in this gene, as well as the angiotensin-converting enzyme (ACE) gene influence the risk of ICVD on smoking status. DNA was analyzed for deletions in the GST M1, T1, and ACE genes by polymerase chain reaction (PCR). No significant association was observed between GST null genotype and ICVD, even in smokers. However, a significant association between ACE and ICVD was observed only in smokers (chi(2) = 0.023, p < 0.05). We conclude that GST polymorphism is not a risk factor for the development of ICVD through smoking and suggest a high probability that ACE polymorphism may contribute to the odds of ICVD in smokers.

Carotid atherosclerosis as a risk factor for complex aortic lesions in patients with ischemic cerebrovascular disease.

Aortic arch atherosclerotic lesions can cause ischemic cerebrovascular disease (ICVD). The association between carotid and aortic atherosclerosis was examined, and it was investigated whether noninvasive carotid evaluation aids in the identification of aortic lesions as potential ICVD risk. The subjects comprised 147 patients with ICVD who had undergone carotid ultrasonography and transesophageal echocardiography. Carotid and aortic arch atherosclerosis was evaluated by measuring the maximum intima - media thickness (IMT), with aortic IMT of at least 4 mm, mobile plaques and/or ulcers defined as complex aortic lesions with potential ICVD risk. Carotid IMT was linearly associated with aortic IMT (r=0.53, p<0.001), and the association was independent of traditional cardiovascular risk factors (beta =0.36, p<0.001). Also, each 1 SD greater carotid IMT was associated with 4.2-fold (95% confidence interval: 2.5-7.0) higher likelihood of complex aortic lesions, with the likelihood little modified when controlling for cardiovascular risk factors. In particular, complex aortic lesions were found in 78% of patients with the highest carotid IMT tertile, compared with 14% of those with the lowest tertile (p<0.05). Based on these findings, carotid atherosclerosis is associated with aortic atherosclerosis, representing a risk factor for aortic lesions that are a potential ICVD risk.

Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese.

Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of ischemic cerebrovascular disease and atherosclerosis. Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism. Several studies have recently reported the presence of a relationship between Ser447Stop mutation of LPL and coronary artery disease. Other polymorphisms (HindIII and PvuII) of the LPL gene have already been shown to correlate significantly with dyslipidemia. We investigated whether these polymorphisms are associated with increased risk of ischemic cerebrovascular disease (CVD). We recruited 177 CVD patients (atherothrombotic infarction, n=71; cardioembolic infarction, n=30; lacunar infarction, n=76) and 177 healthy control subjects. Subjects were genotyped for the Ser447Stop mutation and for HindIII/PvuII restriction fragment length polymorphisms of the LPL gene, and the findings were investigated for associations with the clinical subtypes of CVD and with lipid levels. The Ser447Stop mutation correlated significantly with CVD (0.107 versus 0.158; P=0.035). For the CG+GG versus CC genotype, the odds ratio between control subjects and CVD patients with atherothrombotic infarction was 0.42 (95% CI, 0.18 to 0.99) (P=0.046). Serum HDL cholesterol and triglyceride levels did not correlate significantly with the Ser447Stop genotype. HindIII polymorphism correlated significantly with CVD (0.234 versus 0.169; P=0.031), but the frequency of PvuII polymorphism was not significantly different between groups. Our results suggest that the Ser447Stop mutation of the LPL gene is a novel genetic marker for low risk of atherothrombotic cerebral infarction.

Angiotensinogen mutations and risk for ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease. Six case-control studies from the Copenhagen City Heart Study.

The M235T and T174M angiotensinogen mutations have been linked to increased risk for ischemic heart and cerebrovascular disease. To determine whether angiotensinogen mutations are associated with ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease. Six case-control studies from the Copenhagen City Heart Study. Copenhagen, Denmark. Participants in the Copenhagen City Heart Study and patients from the same hospital with ischemic heart disease (n = 866 and n = 943, respectively), myocardial infarction (n = 519 and n = 493, respectively), or ischemic cerebrovascular disease (n = 489 and n = 434, respectively) and 7975 controls without these conditions. Genotypes for the M235T and T174M angiotensinogen mutations were compared between controls and Copenhagen City Heart Study participants with ischemic heart disease, myocardial infarction, and cerebrovascular disease (studies 1a, 1b, and 1c) and patients from Copenhagen University Hospital with the same conditions (studies 2a, 2b, and 2c). Relative allele frequencies of 235T and 174M in the general population were 0.41 and 0.12, respectively. Genotype was not associated with increased risk for ischemic heart or ischemic cerebrovascular disease in studies of either mutation alone or combined in women or men. Among compound heterozygotes (235MT /174TM ), women in case-control study 2a had decreased risk for ischemic heart disease in age-adjusted analysis; however, this decreased risk was not seen in multifactorial-adjusted or matched analyses, in men, or in case-control study 1a. Among double homozygotes (235TT /174MM ), women in case-control study 2b had increased risk for myocardial infarction in matched analysis; however, this increased risk was not seen in age- or multifactorial-adjusted analyses, in men, or in case-control study 1b. Among single homozygotes (235TT /174TT ), men in case-control study 2b had increased risk for myocardial infarction in multifactorial-adjusted and matched analyses. This risk was not present in age-adjusted analysis, in women, or in case-control study 1b. In addition, male single homozygotes had decreased risk for ischemic cerebrovascular disease in case-control study 2c in age- and multifactorial-adjusted analyses, but this finding was not seen in matched analysis, in women, or in case-control study 1c. In six large case-control studies, the M235T and T174M angiotensinogen mutations were not consistently associated with increased (or decreased) risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease. Statistically significant associations may represent chance findings rather than real phenomena.

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

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. 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. 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%. 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.

A common mutation in lipoprotein lipase confers a 2-fold increase in risk of ischemic cerebrovascular disease in women but not in men.

We previously showed that the common Asn291Ser substitution in lipoprotein lipase is associated with elevated plasma triglyceride levels and a 2-fold increase in the risk of ischemic heart disease in women but not men. In this study, we tested the hypothesis that this substitution is also associated with an increased risk of ischemic cerebrovascular disease (ICVD). We compared 260 patients who had nonfatal ICVD and carotid stenosis >/=50% with 1560 age-matched controls and also compared 205 Copenhagen City Heart Study cases who had nonfatal ICVD with 1210 age-matched controls. All subjects were white and from Denmark. Overall, no significant difference was observed between carrier frequencies among those with and without ICVD; however, sex interacted with genotype in predicting ICVD in the ICVD and carotid stenosis cases (P=0.02). In Copenhagen City Heart Study cases, sex was not significant (P=0.18). Odds ratios for ICVD in female mutation carriers were 2.9 (95% confidence interval [CI], 1.3 to 6. 4) and 1.9 (95% CI, 0.8 to 4.6) in ICVD plus carotid stenosis cases and Copenhagen City Heart Study cases, respectively. Equivalent values in male mutation carriers were 0.8 (95% CI, 0.3 to 1.8) and 0.8 (95% CI, 0.3 to 2.0), respectively. These results were similar in analyses that also allowed for other conventional cardiovascular risk factors. These results suggest that the Asn291Ser substitution in lipoprotein lipase is not associated with nonfatal ICVD in men but that it possibly confers a 2-fold risk in women.