Variations in the noncoding single-nucleotide polymorphisms (SNPs) at positions 560 and 832 in the 5' promoter region of the apolipoprotein E gene define genotypes that distinguish between high and ...low concentrations of plasma total and high-density lipoprotein cholesterol and triglycerides. We addressed whether these genotypes improve the prediction of ischemic heart disease (IHD) in subsamples of individuals defined by traditional risk factors and the genotypes defined by the epsilon(2), epsilon(3), and epsilon(4) alleles in exon 4 of the apolipoprotein E gene.
In a sample of 3686 female and 2772 male participants of the Copenhagen City Heart Study who were free of IHD events, 576 individuals (257 women, 7.0% and 319 men, 11.5%) were diagnosed as having developed IHD in 6.5 years of follow-up. Using a stepwise Patient Rule-Induction Method modeling strategy that acknowledges the complex pathobiology of IHD, we identified a subsample of 764 elderly women (> or =65 years) with hypertriglyceridemia who had a history of smoking, a history of hypertension, or a history of both in which the A(560)T(832)/A(560)T(832) and A(560)T(832)/A(560)G(832) 5' 2-SNP genotypes had a higher cumulative incidence of IHD (172/1000) compared to the incidence of 70/1000 in the total sample of women.
Our study validates that 5' apolipoprotein E genotypes improve the prediction of IHD and documents that the improvement is greatest in a subset defined by a particular combination of traditional risk factors in Copenhagen City Heart Study female participants. We discuss the use of these genotypes in medical risk assessment of IHD in the population represented by the Copenhagen City Heart Study.
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.
Except for the rare ε22 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 ε22, ε32, ε42, ε33, ε43, and ε44 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 (χ
2:
P=0.01) and hypertriglyceridemic patients (χ
2:
P<0.001). By comparison with ε33, ε44 predicted a 2-fold increase whereas ε32 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, ε22, ε42, ε43, and ε44 versus ε33 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 ε44 raises cholesterol levels, ε32 reduces cholesterol levels, and ε22, ε42, ε43, and ε44 raise triglyceride levels in comparison with ε33. These data suggest that hypercholesterolemic individuals carrying ε44 and hypertriglyceridemic individuals carrying ε22, ε42, ε43, or ε44 are relatively more often referred to lipid clinics than carriers of ε33.
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