Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease.

Abstract

Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart disease (IHD). We tested whether common genetic variation in the apolipoprotein A1 gene (APOA1) contributes to apoA-I and HDL cholesterol levels and risk of IHD in the general population. We resequenced the regulatory and coding regions of APOA1 in 190 individuals from the Copenhagen City Heart Study with the lowest 1% (n=95) and highest 1% (n=95) apoA-I levels. Two single-nucleotide polymorphisms (SNPs) were subsequently genotyped in the Copenhagen City Heart Study (n=10,273) and in 2361 cases with IHD (the Copenhagen Ischemic Heart Disease Study). In total, 13 genetic variants were identified. Three SNPs, g.-560A→C, g.-151C→T, and *181A→G, determined a haplotype that differed between high and low apoA-I groups (6 vs. 1%, P=0.002). Genotype combinations of two SNPs, the g.-560A→C (tagging the g.-560A→C/g.-151C→T/*181A→G haplotype) and g.-310G→A (situated near a potential functional promoter site), were associated with increases in apoA-I and HDL cholesterol levels of up to 6.6 and 8.5%, respectively, resulting in theoretically predicted reductions in risk of 9 and 8% for IHD and 14 and 12% for myocardial infarction (MI). Despite this, these same genotype combinations were not associated with decreased risk of IHD or MI. Common genetic variation in APOA1 associated with increased apoA-I and HDL cholesterol levels did not associate with decreased risk of IHD or MI.