Comprehensive Evaluation of the Association of <i>APOE</i> Genetic Variation with Plasma Lipoprotein Traits in U.S. Whites and African Blacks

<div><p>Although common <i>APOE</i> genetic variation has a major influence on plasma LDL-cholesterol, its role in affecting HDL-cholesterol and triglycerides is not well established. Recent genome-wide association studies suggest that <i>APOE</i> also affects plasma variation in HDL-cholesterol and triglycerides. It is thus important to resequence the <i>APOE</i> gene to identify both common and uncommon variants that affect plasma lipid profile. Here, we have sequenced the <i>APOE</i> gene in 190 subjects with extreme HDL-cholesterol levels selected from two well-defined epidemiological samples of U.S. non-Hispanic Whites (NHWs) and African Blacks followed by genotyping of identified variants in the entire datasets (623 NHWs, 788 African Blacks) and association analyses with major lipid traits. We identified a total of 40 sequence variants, of which 10 are novel. A total of 32 variants, including common tagSNPs (≥5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations. Other than the established associations of <i>APOE*2</i> and <i>APOE*4</i> with LDL-cholesterol, we have identified additional independent associations with LDL-cholesterol. We have also identified multiple associations of uncommon and common <i>APOE</i> variants with HDL-cholesterol and triglycerides. Our comprehensive sequencing and genotype-phenotype analyses indicate that <i>APOE</i> genetic variation impacts HDL-cholesterol and triglycerides in addition to affecting LDL-cholesterol.</p>