title: APP and BACE1 miRNA genetic variability has no major role in risk for Alzheimer disease.
abstract: Expression levels of the amyloid precursor protein (APP) and beta-site amyloid (Abeta) cleaving enzyme 1 (BACE1) have been implicated in Alzheimer disease (AD) progression. In a well-characterized Belgian group of 358 AD patients and 462 controls, we examined whether genetic variability in microRNA (miRNA) binding sites of APP and BACE1 or in associated miRNAs influenced risk for AD. Direct sequencing identified six variants in the 3' untranslated region (UTR) of APP and 29 variants in the 3' UTR of BACE1, of which few variants were restricted to patients: in APP; 4 variants in 6 patients ( approximately 2%) and in BACE1; 7 variants in 11 patients ( approximately 3.5%). Further genetic screening of the miR-29 cluster encoding the miR-29a/b-1 genes showed 10 variants in close proximity of this cluster. Association studies using all common variants detected in the 3' UTR of BACE1 and the miR-29 gene cluster did not identify an association with AD risk. However, we did observe statistical interaction between rs535860 (BACE1 3' UTR) and rs34772568 (near miR29a; odds ratio [OR](interaction), 0.4; 95% confidence interval [CI], 0.17-0.96; P=0.033). While the exact role of the patient-specific miRNA variants within the 3' UTR region of APP and BACE1 demands further analyses, this study does not support a major contribution of miRNA genetic variability to AD pathogenesis.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Bettens
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Helen
authors.initials: H
authors.lastname: Van Miegroet
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001483:Base Sequence; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged
chemical_list: D020413:3' Untranslated Regions; D016564:Amyloid beta-Protein Precursor; D035683:MicroRNAs; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human