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BACKGROUND - The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.
METHODS AND RESULTS - We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10) and 1.4% reduced carotid intima-media thickness (P=4×10) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10).
CONCLUSIONS - Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
© 2016 American Heart Association, Inc.
OBJECTIVE - To determine apolipoprotein E (APOE)-epsilon4 and -epsilon2 frequencies and risk of mild cognitive impairment (MCI) and dementia in Shanghai, China.
METHODS - A total of 34 MCI and 34 dementia cases were recruited from an urban Memory Disorders Clinic and 32 controls were recruited from a residential community served by the clinic. Apolipoprotein E was genotyped using standard methods.
RESULTS - Among controls, frequencies were epsilon2, 0.11; epsilon3, 0.84; and epsilon4, 0.05; among MCI, 0.05, 0.77, and 0.18; and for dementia, 0.02, 0.84, and 0.15, respectively. In education-adjusted models, the odds ratio (OR) = 5.6 for dementia (95% CI = 1.09-29.3) and 4.7 for MCI (95% CI = 0.90-25.2) associated with any epsilon4 allele. The epsilon2 allele was inversely associated with dementia (OR = 0.12, 95% CI = 0.013-0.997) and MCI (OR = 0.38, 95% CI = 0.08-1.61).
CONCLUSIONS - APOE-epsilon4 increases and -epsilon2 decreases the risk of dementia vs normal cognition. Similar trends were observed for amnestic mild cognitive impairment (aMCI).
Human apoE is a multifunctional and polymorphic protein synthesized and secreted by liver, brain, and tissue macrophages. Here we show that apoE isoforms and mutants expressed through lentiviral transduction display cell-specific differences in secretion efficiency. Whereas apoE3, apoE4, and a natural mutant of apoE4 (apoE-Cys(142)) were efficiently secreted from macrophages, apoE2 and a non-natural apoE mutant (apoE-Cys(112)/Cys(142)) were retained in the perinuclear region and only minimally secreted. The secretory block for apoE2 in macrophages was not affected by the ablation of LDLR (low density lipoprotein receptor), ABCA-1, or SR-BI (scavenger receptor class B type I) but was released in the absence of low density lipoprotein receptor related protein (LRP). In co-immunoprecipitation experiments, an anti-apoE antibody pulled down two times more LRP in apoE2-transduced macrophages than in apoE3-expressing macrophages. Non-reducing SDS-PAGE/Western blot analyses showed that macrophage apoE2 is mostly dimeric and multimeric, whereas apoE3 is predominantly monomeric. ApoE2 retention and multimer formation also occurred in human macrophages derived from the monocyte cell line THP-1. These results were specific for macrophages, as in transduced mouse primary hepatocytes: 1) ApoE2 was secreted as efficiently as apoE3 and apoE4; 2) all isoforms were exclusively in monomeric form; 3) there was no co-immunoprecipitation of apoE and LRP. A microsomal triglyceride transfer protein (MTP) inhibitor nearly deleted apoB100 secretion from hepatocytes without affecting apoE secretion. These data show that macrophages retain apoE2, a highly expressed protein carried by about 8% of the human population. Given the role of locally produced apoE in regulating cholesterol efflux, modulating inflammation, and controlling oxidative stress, this unique property of apoE2 may have important impacts on atherogenesis.