TY - JOUR

T1 - Context-dependent associations between variation in risk of ischemic heart disease and variation in the 5' promoter region of the apolipoprotein E gene in Danish women

AU - Stengård, Jari H

AU - Dyson, Greg

AU - Frikke-Schmidt, Ruth

AU - Tybjaerg-Hansen, Anne

AU - Nordestgaard, Borge G

AU - Sing, Charles F

AU - Stengård, Jari H

AU - Dyson, Greg

AU - Frikke-Schmidt, Ruth

AU - Tybjærg-Hansen, Anne

AU - Nordestgaard, Borge G

AU - Sing, Charles F

N1 - Keywords: Age Factors; Aged; Algorithms; Alleles; Apolipoproteins E; Denmark; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Polymorphism, Single Nucleotide; Predictive Value of Tests; Promoter Regions, Genetic; Risk Factors; Triglycerides

PY - 2010/2/1

Y1 - 2010/2/1

N2 - OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

AB - OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

U2 - 10.1161/CIRCGENETICS.109.862748

DO - 10.1161/CIRCGENETICS.109.862748

M3 - Journal article

C2 - 20160192

VL - 3

SP - 22

EP - 30

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

SN - 1942-325X

IS - 1

ER -