Premium
P1‐083: Association of CYP2D6∗3 and CYP2D6∗10 genetic polymorphism on the Donepezil metabolism with Alzheimer's patients
Author(s) -
Vivekanandhan Subbiah,
Sonali Nirmal,
Murali Munisamy,
Manjari Tripathi
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.631
Subject(s) - donepezil , cyp2d6 , pharmacology , dementia , medicine , polymorphism (computer science) , population , genotype , drug , pharmacokinetics , alzheimer's disease , disease , oncology , biology , genetics , cytochrome p450 , metabolism , environmental health , gene
Background: Sortilin-related receptor, Sorl1, is a neuronal receptor that interacts with the amyloid precursor protein to regulate amyloidogenesis. Reduced expression of Sorl1 is associated with amyloid beta (Ab) deposition and several recent studies have shown that variants in the gene encoding Sorl1 are associated with Alzheimer’s disease (AD) in different ethnic groups. However, little is known about the effect of SORL1 gene variants on modifying changes in brain magnetic resonance imaging (MRI) scans. Methods: A cohort of 292 Australian individuals aged 75 and over, and with known dementia status were drawn from a larger longitudinal study, the Sydney Older Persons Study (SOPS). Participants provided a blood sample from which DNA was extracted and used for genotyping. A sub-sample also underwent a brain MRI scan (n 1⁄4 128). The relationships between SORL1 genotypes and associated haplotypes with dementia (N 1⁄4 292) and brain MRI measures (n 1⁄4 128) were determined. Results: None of the SNPs was significant in association with dementia unless when stratified for sex. However, One haplotype was associated with dementia (H1: P 1⁄4 0.021, OR 1⁄4 1.54). WMHs analyses revealed significant results of genetic association with all the SNPs after controlling for sex and dementia status. (rs4935774: P 1⁄4 0.025; rs2298813: P 1⁄4 0.034; rs1133174: P 1⁄4 0.046). Moreover, 3 haplotypes were significant with temporal or frontal WMHs (H1: P 1⁄4 0.10; H2: P 1⁄4 0.032; H3: P 1⁄4 0.001). To replicate these results, associations between SNPs in the SORL1 gene and WMHs will be investigated in the Sydney Memory and Ageing Study. This study comprises 1037 community-dwelling adults aged 70-90, 53% of whom underwent MRI scans. Nearly all participants provided a genomic DNA sample. Over 190 of SORL1 SNPs are being genotyped with the Affymetrix Gene Array 6.0. One of the SNPs genotyped in SOPS cohort is part of 85 SNPs directly represented on the array. Other SNPs will be imputed with 144 SNPs in linkage disequilibrium using PLINK software. Conclusions: The results provide preliminary evidence that sortilin-related receptor gene variants are associated with brain WMHs and possibly dementia.