Influence of rs1080985 single nucleotide polymorphism of the CYP2D6 gene on response to treatment with donepezil in patients with Alzheimer’s disease

Abstract

BackgroundRecent data indicate that the rs1080985 single nucleotide polymorphism of the cytochrome P450 (CYP) 2D6 gene may affect the response to treatment with donepezil in patients with Alzheimer’s disease. There is also evidence that the common apolipoprotein E (APOE) polymorphism may affect the response to treatment with donepezil in Alzheimer’s disease. We investigated the association between response to donepezil and the rs1080985 single nucleotide polymorphism, the minor allele (G) of which was previously reported to be associated with a poor response to this drug in patients with Alzheimer’s disease. The common APOE polymorphism was also assessed for its relevance to the outcome of this treatment.MethodsAnalysis of CYP2D6 and APOE polymorphisms was undertaken in 88 naive Caucasian patients with Alzheimer’s disease. All patients received treatment with donepezil for at least 10 months, and the response to treatment was then assessed according to the National Institute for Health and Clinical Excellence criteria.ResultsNo significant differences were observed in distribution of the CYP2D6 rs1080985 single nucleotide polymorphism or common APOE polymorphism between responders (68.2%) and nonresponders (31.8%) to treatment with donepezil.ConclusionOur results suggest that neither the CYP2D6 nor the APOE polymorphism influences the response to treatment with donepezil in a Polish population with Alzheimer’s disease.

Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms

“…In this study, no difference was observed in the clinical response, regardless of the presence of APOE4 (Table 5). Our findings are different from those obtained by other investigators [30,31], but are in line with the results reported by Rigaud et al [29], Klimkowicz-Mrowiec et al [32], and Lu et al [33]. Lu and colleagues [33] also analyzed the influence of the 3 allele in clinical response and found an increase in the rate of good responders among non-carriers of 3 taking donepezil, a result that was not reproduced in the present study.…”

Influence of the rs1080985 Single Nucleotide Polymorphism of the CYP2D6 Gene and APOE Polymorphism on the Response to Donepezil Treatment in Patients with Alzheimer's Disease in China

“…However, the effect was found to be small to moderate. Similar to a study in Polish individuals [ 12 ], findings did not show a significant role of the minor allele in improving the clinical response to donepezil. These contrasting findings suggest that there are additional factors, probably genetic factors that are correlated with ethnicity which are involved in the response to donepezil treatment.…”

“…Three studies that have analyzed the interaction between APOE status and rs1080985 did not find a direct interaction between APOE and CYP2D6 polymorphisms [ 11 , 12 , 13 ]. In one of these studies, a marginal significance (p = 0.05) for frequency of the APOE- Ɛ4 and rs1080985 G allele was found, but an independent effect of APOE -Ɛ4 on response to donepezil was not found [ 12 ]. In our study, APOE -Ɛ4 was not significantly associated with the therapeutic response to donepezil.…”

“…The gene located on chromosome 22q13.1-13.2 is highly polymorphic, with the G allele of the single nucleotide polymorphism (SNP) rs1080985 (C -1584 → G) in the promoter region of the CYP2D6 gene associated with higher gene expression and greater enzymatic activity in vivo [ 8 ]. This SNP has also been associated with a poorer response to donepezil in Italian patients with AD [ 9 , 10 , 11 ], yet found to play no effect in 88 Polish patients [ 12 ]. To our knowledge, there are no current published findings examining this association in the Chinese population.…”

Clinical implications of neuropharmacogenetics

“…Most of these studies show evidence of better responses in poor metabolisers although one study found a trend in the opposite direction [29] and no association was found in another study [15].…”