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.
| Original language | English |
|---|---|
| Journal | Neurobiology of Aging |
| Volume | 34 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2013 |
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Keywords
- Acetylcholinesterase inhibitors
- Alzheimer's disease
- Genetics
- Genome-wide association study
- Pharmacogenomics
ASJC Scopus subject areas
- Clinical Neurology
- Neuroscience(all)
- Ageing
- Developmental Biology
- Geriatrics and Gerontology
Cite this
Pharmacogenomics in Alzheimer's disease : A genome-wide association study of response to cholinesterase inhibitors. / Martinelli-Boneschi, Filippo; Giacalone, Giacomo; Magnani, Giuseppe; Biella, Gloria; Coppi, Elisabetta; Santangelo, Roberto; Brambilla, Paola; Esposito, Federica; Lupoli, Sara; Clerici, Francesca; Benussi, Luisa; Ghidoni, Roberta; Galimberti, Daniela; Squitti, Rosanna; Confaloni, Annamaria; Bruno, Giuseppe; Pichler, Sabrina; Mayhaus, Manuel; Riemenschneider, Matthias; Mariani, Claudio; Comi, Giancarlo; Scarpini, Elio; Binetti, Giuliano; Forloni, Gianluigi; Franceschi, Massimo; Albani, Diego.
In: Neurobiology of Aging, Vol. 34, No. 6, 06.2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pharmacogenomics in Alzheimer's disease
T2 - A genome-wide association study of response to cholinesterase inhibitors
AU - Martinelli-Boneschi, Filippo
AU - Giacalone, Giacomo
AU - Magnani, Giuseppe
AU - Biella, Gloria
AU - Coppi, Elisabetta
AU - Santangelo, Roberto
AU - Brambilla, Paola
AU - Esposito, Federica
AU - Lupoli, Sara
AU - Clerici, Francesca
AU - Benussi, Luisa
AU - Ghidoni, Roberta
AU - Galimberti, Daniela
AU - Squitti, Rosanna
AU - Confaloni, Annamaria
AU - Bruno, Giuseppe
AU - Pichler, Sabrina
AU - Mayhaus, Manuel
AU - Riemenschneider, Matthias
AU - Mariani, Claudio
AU - Comi, Giancarlo
AU - Scarpini, Elio
AU - Binetti, Giuliano
AU - Forloni, Gianluigi
AU - Franceschi, Massimo
AU - Albani, Diego
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - Acetylcholinesterase inhibitors
KW - Alzheimer's disease
KW - Genetics
KW - Genome-wide association study
KW - Pharmacogenomics
UR - http://www.scopus.com/inward/record.url?scp=84875240626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875240626&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2012.12.008
DO - 10.1016/j.neurobiolaging.2012.12.008
M3 - Article
VL - 34
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 6
ER -