title: Identification of a functional apolipoprotein E promoter polymorphism regulating plasma apolipoprotein E concentration.
abstract: OBJECTIVE
  There is compelling evidence that the plasma apolipoprotein E (APOE) concentration, in addition to the APOE ε2/ε3/ε4 genotype, influences plasma lipoprotein levels, but the functional genetic variants influencing the plasma APOE concentration have not been identified.
  
  
  RESULTS
  Genome-wide association studies in 2 cohorts of healthy, middle-aged subjects identified the APOE locus as the only genetic locus showing robust associations with the plasma APOE concentration. Fine-mapping of the APOE locus confirmed that the rs7412 ε2-allele is the primary genetic variant responsible for the relationship with plasma APOE concentration. Further mapping of the APOE locus uncovered that rs769446 (-427T/C) in the APOE promoter is independently associated with the plasma APOE concentration. Expression studies in 199 human liver samples demonstrated that the rs769446 C-allele is associated with increased APOE mRNA levels (P=0.015). Transient transfection studies and electrophoretic mobility shift assays in human hepatoma HepG2 cells corroborated the role of rs769446 in transcriptional regulation of APOE. However, no relationships were found between rs769446 genotype and plasma lipoprotein levels in 2 cohorts (n=1648 and n=1039) of healthy middle-aged carriers of the APOE ε3/ε3 genotype.
  
  
  CONCLUSIONS
  rs769446 is a functional polymorphism involved in the regulation of the plasma APOE concentration.
authors: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Maria Nastase
authors: MN
authors: Mannila
authors: Hovsep
authors: H
authors: Mahdessian
authors: Anders
authors: A
authors: Franco-Cereceda
authors: Gösta
authors: G
authors: Eggertsen
authors: Ulf
authors: U
authors: de Faire
authors: Ann-Christine
authors: AC
authors: Syvänen
authors: Per
authors: P
authors: Eriksson
authors: Anders
authors: A
authors: Hamsten
authors: Ferdinand M
authors: FM
authors: van 't Hooft
mesh_terms: D001057:Apolipoproteins E / Q000097:blood* / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger