title: Pharmacogenomics in Alzheimer's disease: a genome-wide association study of response to cholinesterase inhibitors.
abstract: We conducted a genome-wide association study in a cohort of 176 Italian Alzheimer's disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or ≤1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975A (pcombined = 2.9 × 10(-5), beta regression coefficient: 1.61) and rs17798800A (pcombined = 6.8 × 10(-6), odds ratio = 0.38, 95% confidence interval = 0.25-0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase-anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field.
authors: San Raffaele Scientific Institute, Division of Neuroscience, Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Milan, Italy. martinelli.filippo@hsr.it
authors: Filippo
authors: F
authors: Martinelli-Boneschi
authors: Giacomo
authors: G
authors: Giacalone
authors: Giuseppe
authors: G
authors: Magnani
authors: Gloria
authors: G
authors: Biella
authors: Elisabetta
authors: E
authors: Coppi
authors: Roberto
authors: R
authors: Santangelo
authors: Paola
authors: P
authors: Brambilla
authors: Federica
authors: F
authors: Esposito
authors: Sara
authors: S
authors: Lupoli
authors: Francesca
authors: F
authors: Clerici
authors: Luisa
authors: L
authors: Benussi
authors: Roberta
authors: R
authors: Ghidoni
authors: Daniela
authors: D
authors: Galimberti
authors: Rosanna
authors: R
authors: Squitti
authors: Annamaria
authors: A
authors: Confaloni
authors: Giuseppe
authors: G
authors: Bruno
authors: Sabrina
authors: S
authors: Pichler
authors: Manuel
authors: M
authors: Mayhaus
authors: Matthias
authors: M
authors: Riemenschneider
authors: Claudio
authors: C
authors: Mariani
authors: Giancarlo
authors: G
authors: Comi
authors: Elio
authors: E
authors: Scarpini
authors: Giuliano
authors: G
authors: Binetti
authors: Gianluigi
authors: G
authors: Forloni
authors: Massimo
authors: M
authors: Franceschi
authors: Diego
authors: D
authors: Albani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D002800:Cholinesterase Inhibitors