title: A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease.
abstract: Using a combination of polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing techniques, we identified a unique missense mutation (T-->C) in exon 3 of the APOE gene which resulted in the substitution of pro-28 for leu-28. We screened 1118 White cases of late-onset (>60 years) Alzheimer's disease (AD) from three independent centers (Pittsburgh = 489, Indiana = 319, Mayo Clinic Rochester = 310) and 1123 controls (607 clinically assessed and 516 individuals randomly ascertained from the general population). Two of the 1123 control subjects had the pro-28 mutation (0.18%). However, this mutation was observed in heterozygous state in 2.66, 2.51 and 1.94% of the AD cases from Pittsburgh, Indiana and Mayo Clinic Rochester, respectively, with an overall frequency of 2.42%. All individuals with this mutation were carriers of the APOE*4 allele and hence the mutation was denoted as APOE*4 Pittsburgh (APOE*4P). Compared with the non-E*4P carriers, the E*4P carriers were associated with an increased risk of AD (odds ratio (OR) 13.2) and this risk remained significant even after adjusting for the known effect of APOE*4 (OR 5.4). The risk associated with the E*4P/E*4 combination was about five times (OR 29.1) the risk attributed to APOE*4 carriers alone (OR 5.7). Our data indicates that the new mutation most likely exists in cis-orientation with APOE*4 and is associated with increased risk of developing AD.
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA. ikamboh@helix.hgen.pitt.edu
authors.forename: M I
authors.initials: MI
authors.lastname: Kamboh
authors.forename: C E
authors.initials: CE
authors.lastname: Aston
authors.forename: J
authors.initials: J
authors.lastname: Perez-Tur
authors.forename: E
authors.initials: E
authors.lastname: Kokmen
authors.forename: R E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.forename: S T
authors.initials: ST
authors.lastname: DeKosky
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D019943:Amino Acid Substitution; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D007930:Leucine; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D011392:Proline; D012016:Reference Values; D012042:Registries; D012307:Risk Factors; D014481:United States
chemical_list: D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D011392:Proline; D007930:Leucine