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This article extends the Patient Rule-Induction Method (PRIM) for modeling cumulative incidence of disease developed by Dyson et al. (Genet Epidemiol 31:515-527) to include the simultaneous consideration of non-additive combinations of predictor variables, a significance test of each combination, an adjustment for multiple testing and a confidence interval for the estimate of the cumulative incidence of disease in each partition. We employ the partitioning algorithm component of the Combinatorial Partitioning Method to construct combinations of predictors, permutation testing to assess the significance of each combination, theoretical arguments for incorporating a multiple testing adjustment and bootstrap resampling to produce the confidence intervals. An illustration of this revised PRIM utilizing a sample of 2,258 European male participants from the Copenhagen City Heart Study is presented that assesses the utility of genetic variants in predicting the presence of ischemic heart disease beyond the established risk factors.

Objectives: Characteristic for the genes encoding glutathione S-transferase (GST) M1 and GSTT1 is a null allele, suggested to increase susceptibility to chronic diseases. We report an optimized method for the determination of copy number variation (CNV) in GST genes., Design and Methods: Real-time multiplex PCR reactions were optimized for quantification of GSTM1 and GSTT1 CNV using the DeltaCt method, a fixed volume of diluted DNA, a total volume of 10 microL, 384-well formats, and single determinations of each sample., Results: Consistent genotyping was obtained using DNA in a range of 0.41 ng to 100 ng. In a general population sample of 20,687 individuals the genotype frequencies were concordant with other methods used as standards. Throughput was 4600 genotypes per day at a reagent price of 0.5 euros per sample., Conclusions: This high-throughput, low cost method accurately determines CNV in the GST genes enabling reliable estimates of disease prediction in large epidemiological samples.

Objective: To test the hypothesis that mutations in the vascular endothelial growth factor (VEGF) gene are associated with plasma concentration of VEGF and subsequently the ability to influence coronary collateral arteries in patients with coronary heart disease (CHD)., Methods: Blood samples from patients with chronic ischemic heart disease (n=53) and acute coronary syndrome (n=61) were analysed. Coronary collaterals were scored from diagnostic biplane coronary angiograms., Results: The plasma concentration of VEGF was increased in patients with acute compared to chronic CHD (p=0.01). The genotype frequencies differed significantly from Hardy-Weinberg equilibrium in three of 15 examined loci. Four new mutations in addition to the already described were identified. The VEGF haplotype did not seem to predict plasma VEGF concentration (p=0.5). There was an association between the genotype in locus VEGF-1154 and coronary collateral size (p=0.03) and a significant association between the VEGF plasma concentration and the collateral size (p=0.03)., Conclusion: VEGF plasma concentration seems related to coronary collateral function in patients with CHD. The results did not support the hypothesis that polymorphisms in the untranslated region of the VEGF gene were associated with the concentration of circulating VEGF. Increased understanding of VEGF in the regulation of myocardial collateral flow may lead to new therapies in CHD.

Background: High-density lipoprotein cholesterol (HDLC) is a strong risk factor for atherosclerosis and is assumed to be under considerable genetic control. We aimed to identify gene regions that influence HDLC levels by a genome-wide association analysis in the population-based KORA (Cooperative Health Research in the Region of Augsburg) study., Methods and Results: In KORA S3/F3 (n=1643), we analyzed 377 865 quality-checked single-nucleotide polymorphisms (SNPs; 500K, Affymetrix, Santa Clara, Calif), complemented by the publicly available genome-wide association results from the Diabetes Genetics Initiative (n=2631) and by replication data from KORA S4 (n=4037) and the Copenhagen City Heart Study (n=9205). Among the 13 SNPs selected from the KORA S3/F3 500K probability value list, 3 showed consistent associations in subsequent replications: 1 SNP 10 kb upstream of CETP (pooled probability value=8.5x10(-27)), 1 SNP approximately 40 kb downstream of LIPG (probability value=4.67x10(-10)), both independent of previously reported SNPs, and 1 from an already reported region of LPL (probability value=2.82x10(-11)). Bioinformatical analyses indicate a potential functional relevance of the respective SNPs., Conclusions: The present genome-wide association study identified 2 interesting HDLC-relevant regions upstream of CETP and downstream of LIPG. This draws attention to the importance of long-range effects of intergenic regions, which have been underestimated so far, and may impact future candidate-gene-association studies toward extending the region analyzed. Furthermore, the present study reinforced CETP and LPL as HDLC genes and thereby underscores the power of this type of genome-wide association approach to pinpoint associations of common polymorphisms with effects explaining as little as 0.5% of the HDLC variance in the general population.

Apolipoprotein M (apoM), a 25 kDa plasma protein belonging to the lipocalin protein family, is predominantly associated with HDL. Studies in mice have suggested apoM to be important for the formation of pre-beta-HDL and to increase cholesterol efflux from macrophage foam cells. Overexpression of human apoM in LDL receptor-deficient mice reduced the atherogenic effect of a cholesterol-rich diet. The aim of the present study was to investigate whether the apoM levels in man predict the risk for coronary heart disease (CHD). ApoM was measured in samples from two separate case-control studies. FINRISK '92 consisted of 255 individuals, of whom 80 developed CHD during follow-up and 175 were controls. The Copenhagen City Heart Study included 1,865 individuals, of whom 921 developed CHD during follow-up and 944 were controls. Correlation studies of apoM concentration with several analytes showed a marked positive correlation with HDL and total cholesterol as well as with apoA-I and apoB. There was no significant difference in mean apoM level between CHD and control subjects in either study. In conditional logistic regression analyses, apoM was not a predictor of CHD events, [odds ratio (95% CI) 0.97 (0.74-1.27) and 0.92 (0.84-1.02), respectively]. In conclusion, no association between apoM and CHD could be found in this study.

Objectives: This study was designed to test the hypotheses that single nucleotide polymorphisms (SNPs), in zinc finger protein 202 (ZNF202), predict severe atherosclerosis and ischemic heart disease (IHD)., Background: ZNF202 is a transcriptional repressor controlling promoter elements in genes involved in vascular maintenance and lipid metabolism., Methods: We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis (ankle brachial index >0.7 vs. G altered transcriptional activity of the ZNF202 promoter in vitro., Results: Cross-sectionally, ZNF202 g.-660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 (95% confidence interval [CI]: 1.34 to 3.01). Prospectively, GG versus AA homozygosity predicted a hazard ratio for IHD of 1.21 (95% CI: 1.02 to 1.43). In the 2 case-control studies, the equivalent odds ratios for IHD were 1.29 (95% CI: 1.02 to 1.62) and 1.60 (95% CI: 1.34 to 1.92), confirming the results from the prospective study. Only 2 other SNPs, which were highly correlated with g.-660A>G, also predicted risk of severe atherosclerosis and IHD. Finally, ZNF202 g.-660G versus g.-660A was associated with a 60% reduction in transcriptional activity in vitro, whereas none of the 2 correlated SNPs were predicted to be functional., Conclusions: Homozygosity for a common functional promoter variant in ZNF202 predicts severe atherosclerosis and an increased risk of IHD.

Context: Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear., Objective: To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss-of-function mutations in ABCA1 cause increased risk of ischemic heart disease (IHD)., Design, Setting, and Participants: Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a 31-year prospective general population study (n = 9022; 28 heterozygotes); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (n = 31,241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (n = 16,623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007., Main Outcome Measures: Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype., Results: Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (P < .001). A 17-mg/dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 (95% confidence interval [CI], 1.57-1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 (95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 (95% CI, 0.34-1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 (95% CI, 0.32-2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies (n = 41,961; 6666 cases; 109 heterozygotes) was 0.93 (95% CI, 0.53-1.62)., Conclusion: Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD.

Objective: We tested the hypothesis that 6 nonsynonymous single nucleotide polymorphisms (SNPs) in ATP-Binding-Cassette transporter A1 (ABCA1) affect risk of ischemic heart disease (IHD) in the general population., Methods and Results: We genotyped 9259 individuals from the Danish general population followed for 25 years. Two SNPs (V771M and V825I) were previously associated with increases in HDL-C, 1 (R1587K) with decreased HDL-C, whereas 3 (R219K, I883M and E1172D) did not affect HDL-C levels. Despite this, 5 out of 6 SNPs (V771M, V825I, I883M, E1172D, R1587K) predicted increased risk of IHD. Similar results were obtained in a verification sample with 932 IHD cases versus 7999 controls. A stepwise regression approach identified V771M, I883M, and E1172D as the most important predictors of IHD and additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs., Conclusions: We show that 3 of 6 nonsynonymous SNPs in ABCA1 predict risk of IHD in the general population.

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.

Different combinations of genetic and environmental risk factors are known to contribute to the complex etiology of ischemic heart disease (IHD) in different subsets of individuals. We employed the Patient Rule-Induction Method (PRIM) to select the combination of risk factors and risk factor values that identified each of 16 mutually exclusive partitions of individuals having significantly different levels of risk of IHD. PRIM balances two competing objectives: (1) finding partitions where the risk of IHD is high and (2) maximizing the number of IHD cases explained by the partitions. A sequential PRIM analysis was applied to data on the incidence of IHD collected over 8 years for a sample of 5,455 unrelated individuals from the Copenhagen City Heart Study (CCHS) to assess the added value of variation in two candidate susceptibility genes beyond the traditional, lipid and body mass index risk factors for IHD. An independent sample of 362 unrelated individuals also from the city of Copenhagen was used to test the model obtained for each of the hypothesized partitions., (Copyright (c) 2007 Wiley-Liss, Inc.)

Single nucleotide polymorphisms (SNPs) are hypothesized to explain the genetic predisposition to ischemic heart disease (IHD) in the general population. Lack of evidence for a role of such variation is fostering pessimism about the utility of genetic information in the practice of medicine. In this study we determined the utility of exonic and 5' SNPs in apolipoprotein E (APOE) and lipoprotein lipase (LPL) when considered singly and in combination for predicting incidence of IHD in 8,456 individuals from the general population during 24 years of follow-up. In men, LPL D9N improved prediction of IHD (P = 0.03) beyond smoking, diabetes and hypertension. The group of men heterozygous and homozygous for the rare D9N variant had a hazard ratio (HR) of 1.69 (95% confidence interval = 1.10-2.58) relative to the most common genotype. Pairwise combinations of D9N with -219G > T in APOE and N291S and S447X in LPL significantly improved the prediction of IHD (P = 0.05 in women, P = 0.04 in men, P = 0.03 in men, respectively) beyond smoking, diabetes and hypertension, and identified subgroups of individuals (n = 6-94) with highly significant HRs of 1.92-4.35. These results were validated in a case-control study (n = 8,806). In conclusion, we present evidence that combinations of SNPs in APOE and LPL identify subgroups of individuals at substantially increased risk of IHD beyond that associated with smoking, diabetes and hypertension.

Objective: Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor of genes affecting the vascular endothelium as well as lipid metabolism. A phenotype associated with genetic variation in ZNF202 is presently unknown. We tested the hypothesis that a common variant in ZNF202, A154V, predicts risk of ischemic heart disease (IHD), myocardial infarction (MI), and ischemic cerebrovascular disease (ICVD)., Methods and Results: We conducted a prospective study of more than 9000 individuals from the general population with 24 years follow-up. In women, age-adjusted hazard ratios in heterozygotes and homozygotes versus non-carriers were 1.2 (95% CI: 1.0-1.5, P = 0.04) and 1.5 (1.1-2.1, P = 0.007) for IHD, 1.5 (1.1-2.1; P = 0.01) and 1.7 (1.1-2.8, P = 0.02) for MI, and 1.3 (1.0-1.8, P = 0.07) and 1.3 (0.8-2.1; P = 0.33) for ICVD. Adjustments for lipids and lipoproteins did not alter these hazard ratios substantially. Genotype did not predict risk in men. Finally, results for IHD were borderline significant (P = 0.06) in an independent case-control study including 933 patients and 8068 controls., Conclusion: This is the first study to suggest that ZNF202 could be a new candidate gene for IHD and MI in the general population.

Mutations in the ATP-binding cassette A1 (ABCA1) transporter cause the high-density lipoprotein (HDL) deficiency syndromes of Tangier disease and familial hypoalphalipoproteinemia (FHA). Between individuals carrying ABCA1 mutations, the expression of FHA can be highly variable. Using denaturing HPLC (dHPLC) and direct promoter sequencing we screened the ABCA1 gene of a family with Tangier disease and variable expression of FHA. A new mutation (R1068H) within the first ATP-binding domain was identified in homozygous form in the Tangier disease individual and was present in several family members. Haplotyping of both 1068H alleles in the proband showed homozygosity in the coding region, however, the maternal 1068H allele had three single nucleotide polymorphisms (SNPs) in the promoter previously reported to be associated with reduced ABCA1 expression and HDL levels. An analysis of HDL levels based on 1068H allele haplotype showed the paternal 1068H heterozygotes to have the expected low HDL levels (0.67+/-0.16mmol/L), while maternal 1068H heterozygotes showed normal HDL levels (1.18+/-0.14mmol/L). Haplotype analysis of the wildtype allele amongst heterozygotes showed no haplotype that was common to the paternal or maternal side. We propose that the paternal 1068H ABCA1 allele causes a negative effect on the function of the wildtype allele and is associated with low HDL levels. In contrast, the maternal 1068H allele has less effect and is associated with a relatively normal HDL level. We conclude that haplotypes of mutant ABCA1 alleles may contribute to the phenotypic variance shown between FHA individuals.

Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor that binds elements found predominantly in genes involved in HDL metabolism. We tested the following hypotheses: 1) frequencies of single-nucleotide polymorphisms (SNPs) and haplotypes in ZNF202 differ between individuals with low and high HDL cholesterol; and 2) SNPs in ZNF202 affect HDL cholesterol levels in the general population. We screened the promoter and protein-coding exons of ZNF202 in individuals with the highest 1% (n = 95) and lowest 1% (n = 95) HDL cholesterol among 9,259 Danish adults. None of the 10 SNPs identified differed in frequency as single sites or as haplotypes between low and high HDL cholesterol groups. In accordance with this, seven mutations were equally frequent (4-5%) in individuals with low or high HDL cholesterol. Finally, for all five SNPs identified in the coding region, we determined the association of genotype with HDL cholesterol in 9,259 individuals from the general population. Four SNPs were not associated with variation in HDL cholesterol, although c.*2T>G homozygosity was associated with a discrete effect on HDL cholesterol in men. We show that genetic variation in ZNF202 is common in the general population. However, SNPs in the protein-coding region of ZNF202 do not make a major contribution to HDL cholesterol levels.

The objective of this study was to evaluate 1) whether non single nucleotide polymorphisms-coding (non-cSNP) in the apolipoprotein E gene (APOE) identified by resequencing studies contribute to statistically explaining dyslipidemia if variations in the two cSNPs in exon 4 that define the 2, 3, and 4 alleles are ignored, and 2) whether the contribution of these additional SNPs persists when variations in the cSNPs are considered. We used an ecological, multiple-population, data-mining strategy to identify single-SNP and two-SNP genotypes that distinguish between high and low levels of plasma lipids in three training samples, European-Americans from Rochester, MN, African-Americans from Jackson, MS, and Europeans from North Karelia, Finland. We found that a pair of SNPs located in the 5' region define genotypes A560T832/A560T832, A560T832/A560G832, and A560T832/T560T832, which distinguish between high and low levels of HDL-cholesterol (HDL-C), triglycerides (TG), and/or total cholesterol (T-C). The A560T832/- genotypes predicted high TG and high T-C in both genders in a large independent test sample from Copenhagen, Denmark. Prediction of high T-C in the Danish females was dependent on genotypes defined by the cSNPs. Our study suggests that both regulatory and structural variations should be considered when evaluating the utility of APOE for predicting dyslipidemia in the population at large.

Objectives: We tested whether heterozygosity for the K776N mutation (frequency: 0.4%) in ATP-binding cassette transporter A1 (ABCA1) predicted ischemic heart disease (IHD) in the Copenhagen City Heart Study population., Background: In a complex trait like IHD, genetic variation is considered to be conferred by common DNA polymorphisms, although rare mutations may have a larger impact. Tangier disease, a rare high-density lipoprotein cholesterol (HDL-C) deficiency syndrome with IHD, is caused by homozygous ABCA1 mutations., Methods: We analyzed blood samples from a large cohort study of 9,076 Danish individuals followed for 24 years (167,287 person-years), during which 1,033 incident IHD events occurred. The hypothesis was retested in an independent case-control study comparing 562 IHD patients with 3,103 controls., Results: The cumulative incidence of IHD as a function of age was increased in K776N heterozygotes compared with non-carriers (log-rank test: p = 0.005). At the age of 80 years, 48% of heterozygotes and 23% of non-carriers had IHD. Incidence rates in non-carriers and K776N heterozygotes were 61 and 157 per 10,000 person-years. The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5). Adjusting for HDL-C, or for smoking, diabetes, and hypertension did not change the result, suggesting that genotype predicted risk of IHD beyond that offered by HDL-C, and by other conventional risk factors. Similar trends were obtained in an independent case-control study., Conclusions: Heterozygosity for an ABCA1 mutation (K776N) conferred two- to three-fold risk of IHD in 37 participants in the Copenhagen City Heart study.

Homozygosity for mutations in ABC transporter A1 (ABCA1) causes Tangier disease, a rare HDL-deficiency syndrome. Whether heterozygosity for genetic variation in ABCA1 also contributes to HDL cholesterol (HDL-C) levels in the general population is presently unclear. We determined whether mutations or single-nucleotide polymorphisms (SNPs) in ABCA1 were overrepresented in individuals with the lowest 1% (n=95) or highest 1% (n=95) HDL-C levels in the general population by screening the core promoter and coding region of ABCA1. For all nonsynonymous SNPs identified, we determined the effect of genotype on lipid traits in 9,259 individuals from the general population. Heterozygosity for ABCA1 mutations was identified in 10% of individuals with low HDL-C only. Three of 6 nonsynonymous SNPs (V771M, V825I, and R1587K) were associated with increases or decreases in HDL-C in women in the general population and some with consistent trends in men, determined as isolated single-site effects varying only at the relevant SNP. Finally, these results were consistent over time. In conclusion, we show that at least 10% of individuals with low HDL-C in the general population are heterozygous for mutations in ABCA1 and that both mutations and SNPs in ABCA1 contribute to HDL-C levels in the general population.

In the present study of 9,000 individuals representative of the general population, we have considered whether the addition of common single nucleotide polymorphisms (SNPs) in the promoter region of Apolipoprotein E (APOE) improve the statistical explanation of variation in lipid traits and test the hypothesis that the estimated genotype effects are independent of factors indexed by gender and age. To address these questions, we have asked, for each gender and for each 20-year age strata (young: 20-39 years; middle-aged: 40-59 years; old: 60-79 years; very old: 80-100 years), how much trait variation is associated with the traditional epsilon2, epsilon3, and epsilon4 allelic variations defined by the g.2059T --> C and g.2197C --> T SNPs in the fourth exon of the APOE gene, and how much additional trait variation is associated with genotypes defined by combining the g.2059T --> C and g.2197C --> T SNPs with one, two, or three promoter SNPs. Our study demonstrates that the pleiotropic effects of genotype variation defined by the traditional epsilon2, epsilon3, and epsilon4 alleles on five plasma measures of lipid metabolism manifest differently in women and men and change significantly during the life cycle for high-density lipoprotein cholesterol in women. Multi-site genotypes defined by adding SNPs located in the 5' promoter region to the traditional g.2059T --> C and g.2197C --> T SNPs doubled the estimate of genetic variance of high-density lipoprotein and apolipoprotein Al in middle-aged females.

Background: More than 600 different, but rare, mutations in the low-density lipoprotein (LDL) receptor have been identified as the cause of familial hypercholesterolaemia. In contrast, only a single common amino acid-changing polymorphism (A370T) has been reported in this gene. The association of this polymorphism with variations in lipid levels is at present unclear., Methods: We obtained genotypes for 9238 individuals from The Copenhagen City Heart Study, of which 465 had stroke and 1019 had ischaemic heart disease., Results: In this cohort from the Danish general population, 90.2% (n = 8,332), 9.5% (n = 875), and 0.3% (n = 31) were 370A homozygotes, A370T heterozygotes, and 370T homozygotes, respectively. The incidences of stroke in 370A homozygotes, A370T heterozygotes, and 370T homozygotes were 28, 26, and 100 per 10,000 person-years, respectively (370T homozygotes vs. 370A homozygotes: log-rank, P = 0.002). The relative risk and odds ratio for stroke in 370T homozygotes vs. 370A homozygotes were 3.6 (95% confidence interval, 1.5-8.8) and 3.6 (95% confidence interval, 1.3-9.8) in prospective and cross-sectional studies, respectively. Furthermore, average age at onset of stroke in 370T homozygotes tended to be lower than in heterozygotes and 370A homozygotes combined (59 vs. 66 years, P = 0.08). In contrast, neither levels of cholesterol, LDL cholesterol, apolipoprotein B, or triglycerides, nor risk of ischaemic heart disease was associated with genotype., Conclusion: This is the first prospective study to suggest an association between a polymorphism in the LDL receptor and stroke. Because this association is independent of lipid levels, our results point toward a hitherto unknown function of this receptor in the brain.

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.

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., (Copyright 1999 Lippincott Williams & Wilkins)

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.