Replication Study to Confirm the Role of CYP2D6 Polymorphism rs1080985 on Donepezil Efficacy in Alzheimer's Disease Patients

Albani, Diego; Boneschi, Filippo Martinelli; Biella, Gloria; Giacalone, Giacomo; Lupoli, Sara; Clerici, Francesca; Benussi, Luisa; Ghidoni, Roberta; Galimberti, Daniela; Squitti, Rosanna; Mariani, Stefania; Confaloni, Annamaria; Bruno, Giuseppe; Mariani, Claudio; Scarpini, Elio; Binetti, Giuliano; Magnani, Giuseppe; Franceschi, M.; Forloni, Gianluigi

doi:10.3233/jad-2012-112123

Cited by 35 publications

(25 citation statements)

References 21 publications

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“…In one of these studies, a marginal significance for frequency of the APOE ε4 and rs1080985 G allele was found, but an independent effect of APOE ε4 on response to donepezil was not found 8. In our study, APOE ε4 was not significantly associated with the therapeutic response to donepezil.…”

Section: Discussioncontrasting

confidence: 71%

“…Two studies that analyzed the interaction between APOE status and rs1080985 did not find a direct interaction between APOE and CYP2D6 polymorphisms 7,8. In one of these studies, a marginal significance for frequency of the APOE ε4 and rs1080985 G allele was found, but an independent effect of APOE ε4 on response to donepezil was not found 8.…”

Section: Discussionmentioning

confidence: 96%

“…The influence of rs1080985 on response to treatment with donepezil was assessed in three Italian studies 6–8. The frequency of the G allele was higher in nonresponders than in responders, and the presence of the G allele was associated with a poor response to treatment with donepezil; however, the effect size of the modulation of donepezil response was small to moderate.…”

Section: Discussionmentioning

confidence: 99%

“…This locus is highly polymorphic, with a large number of allelic variants identified and resulting in different degrees of enzymatic activity 3. The G allele of the single nucleotide polymorphism, rs1080985 (C −1584 →G), in the promoter region of the CYP2D6 gene, was associated with higher gene expression and greater enzymatic activity in vivo 45 and a poor response to treatment with donepezil in Italian patients with Alzheimer’s disease 6–8…”

Section: Introductionmentioning

confidence: 99%

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

Klimkowicz‐Mrowiec¹,

Wołkow²,

Sado³

et al. 2013

NDT

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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.

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Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Klimkowicz‐Mrowiec¹,

Wołkow²,

Sado³

et al. 2013

NDT

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“…CYP2D6 variants affect donepezil effi cacy and safety in AD [3,13,17,18,22,26,53,57]. The common variant rs1080985 of CYP2D6 is associated with poor response to donepezil [58,59]. A higher frequency of mutated CYP2D6 allele *2A was found in responder than in nonresponder patients (75.38 vs 43.48%) [60].…”

Section: Pathogenic Genesmentioning

confidence: 99%

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

et al. 2016

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The practical pharmacogenetics of Alzheimer's disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aβ treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug-drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.

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Pharmacogenomics of Alzheimer’s Disease: Novel Therapeutic Strategies for Drug Development

Cacabelos

Torrellas

et al. 2014

Methods in Molecular Biology

165

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Alzheimer's disease (AD) is a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis, and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. As a complex disorder, AD is a polygenic and multifactorial clinical entity in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions, lead to amyloid deposition, neurofibrillary tangle formation, and premature neuronal death, the major neuropathological hallmarks of AD. Future perspectives for the global management of AD predict that genomics and proteomics may help in the search for reliable biomarkers. In practical terms, the therapeutic response to conventional drugs (cholinesterase inhibitors, multifactorial strategies) is genotype-specific. Genomic factors potentially involved in AD pharmacogenomics include at least five categories of gene clusters: (1) genes associated with disease pathogenesis; (2) genes associated with the mechanism of action of drugs; (3) genes associated with drug metabolism (phase I and II reactions); (4) genes associated with drug transporters; and (5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

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Replication Study to Confirm the Role of CYP2D6 Polymorphism rs1080985 on Donepezil Efficacy in Alzheimer's Disease Patients

Cited by 35 publications

References 21 publications

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

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

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

Pharmacogenomics of Alzheimer’s Disease: Novel Therapeutic Strategies for Drug Development

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Replication Study to Confirm the Role of CYP2D6 Polymorphism rs1080985 on Donepezil Efficacy in Alzheimer's Disease Patients

Cited by 35 publications

References 21 publications

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

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

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

Pharmacogenomics of Alzheimer’s Disease: Novel Therapeutic Strategies for Drug Development

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Product

Resources

About

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

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