Dataset Information

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.

ABSTRACT: BACKGROUND/AIM:Recent data have indicated that the rs1080985 single nucleotide polymorphism (SNP) of the cytochrome P450 (CYP) 2D6 and the common apolipoprotein E (APOE) gene may affect the response to donepezil in patients with Alzheimer's disease (AD). We investigated this association in Chinese patients with mild-to-moderate AD. METHODS:In this prospective cohort study, analyses of CYP2D6 and APOE were conducted in 208 native Chinese patients with mild-to-moderate AD. All patients were treated with donepezil 5 mg/day for 6 months, and the response to treatment was assessed using the Mini-Mental State Examination. RESULTS:No significant differences between responders (68.9%) and nonresponders (31.1%) to donepezil treatment (6 months' duration) were observed in the distribution of the CYP2D6 rs1080985 SNP, common APOE polymorphism or a combination of the two. CONCLUSIONS:Our results suggest that neither the CYP2D6 nor the APOE polymorphism influences the 6-month response to donepezil treatment in a Chinese population with AD.

SUBMITTER: Liu M

PROVIDER: S-EPMC4264516 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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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.

Liu Mengyuan M Zhang Ying Y Huo Ya Ruth YR Liu Shuling S Liu Shuai S Wang Junwei J Wang Change C Wang Jinhuan J Ji Yong Y

Dementia and geriatric cognitive disorders extra 20140901 3

<h4>Background/aim</h4>Recent data have indicated that the rs1080985 single nucleotide polymorphism (SNP) of the cytochrome P450 (CYP) 2D6 and the common apolipoprotein E (APOE) gene may affect the response to donepezil in patients with Alzheimer's disease (AD). We investigated this association in Chinese patients with mild-to-moderate AD.<h4>Methods</h4>In this prospective cohort study, analyses of CYP2D6 and APOE were conducted in 208 native Chinese patients with mild-to-moderate AD. All patie ...[more]

PMID: 25538729

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Project description:BackgroundThe CYP2D6 gene locus has been extensively studied over decades, yet a portion of variability in CYP2D6 activity cannot be explained by known sequence variations within the gene, copy number variation, or structural rearrangements. It was proposed that rs5758550, located 116 kb downstream of the CYP2D6 gene locus, increases gene expression and thus contributes to variability in CYP2D6 activity. This finding has, however, not been validated. The purpose of the study was to address a major technological barrier, i.e., experimentally linking rs5758550, also referred to as the "enhancer" single-nucleotide polymorphism (SNP), to CYP2D6 haplotypes >100 kb away. To overcome this challenge is essential to ultimately determine the contribution of the "enhancer" SNP to interindividual variability in CYP2D6 activity.MethodsA large ethnically mixed population sample (n=3,162) was computationally phased to determine linkage between the "enhancer" SNP and CYP2D6 haplotypes (or star alleles). To experimentally validate predicted linkages, DropPhase2D6, a digital droplet PCR (ddPCR)-based method was developed. 10X Genomics Linked-Reads were utilized as a proof of concept.ResultsPhasing predicted that the "enhancer" SNP can occur on numerous CYP2D6 haplotypes including CYP2D6*1, *2, *5, and *41 and suggested that linkage is incomplete, i.e., a portion of these alleles do not have the "enhancer" SNP. Phasing also revealed differences among the European and African ancestry data sets regarding the proportion of alleles with and without the "enhancer" SNP. DropPhase2D6 was utilized to confirm or refute the predicted "enhancer" SNP location for individual samples, e.g., of n=3 samples genotyped as *1/*41, rs5758550 was on the *41 allele of two samples and on the *1 allele of one sample. Our findings highlight that the location of the "enhancer" SNP must not be assigned by "default." Furthermore, linkage between the "enhancer" SNP and CYP2D6 star allele haplotypes was confirmed with 10X Genomics technology.ConclusionsSince the "enhancer" SNP can be present on a portion of normal, decreased, or no function alleles, the phase of the "enhancer" SNP must be considered when investigating the impact of the "enhancer" SNP on CYP2D6 activity.

Dataset Information

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.

Publications

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.

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