Dataset Information

Polymorphisms of CHAT but not TFAM or VR22 are Associated with Alzheimer Disease Risk.

ABSTRACT: BACKGROUND Alzheimer disease (AD) is a chronic neurodegenerative disease that is one of the most prevalent health problems among seniors. The cause of AD has not yet been elucidated, but many risk factors have been identified that might contribute to the pathogenesis and prognosis of AD. We conducted a meta-analysis of studies involving CHAT, TFAM, and VR22 polymorphisms and AD susceptibility to further understand the pathogenesis of AD. MATERIAL AND METHODS PubMed/Medline, Embase, Web of Science, the Cochrane Library, and Google Scholar were searched for relevant articles. Rs1880676, rs2177369, rs3810950, and rs868750 of CHAT; rs1937 and rs2306604 of TFAM; and rs10997691 and rs7070570 of VR22 are studied in this meta-analysis. RESULTS A total of 51 case-control studies with 16 446 cases and 16 057 controls were enrolled. For CHAT, rs2177369 (G>A) in whites and rs3810950 (G>A) in Asians were found to be associated with AD susceptibility. No association was detected between rs1880676 and rs868750 and AD risk. For TFAM and VR22, no significant association was detected in studied single-nucleotide polymorphisms (SNPs). CONCLUSIONS Rs2177369 and rs3810950 of CHAT are associated with AD susceptibility, but rs1880676 and rs868750 are not. Rs1937 and rs2306604 of TFAM, and rs10997691 and rs7070570 of VR22 are not significantly associated with AD risk.

SUBMITTER: Gao L

PROVIDER: S-EPMC4917321 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Polymorphisms of CHAT but not TFAM or VR22 are Associated with Alzheimer Disease Risk.

Gao Lili L Zhang Yan Y Deng Jinghua J Yu Wenbing W Yu Yunxia Y

Medical science monitor : international medical journal of experimental and clinical research 20160607

BACKGROUND Alzheimer disease (AD) is a chronic neurodegenerative disease that is one of the most prevalent health problems among seniors. The cause of AD has not yet been elucidated, but many risk factors have been identified that might contribute to the pathogenesis and prognosis of AD. We conducted a meta-analysis of studies involving CHAT, TFAM, and VR22 polymorphisms and AD susceptibility to further understand the pathogenesis of AD. MATERIAL AND METHODS PubMed/Medline, Embase, Web of Scienc ...[more]

PMID: 27272392

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Project description:BACKGROUND:Cholinergic hypothesis of Alzheimer's disease (AD) is based on the findings that a reduced and/or perturbed cholinergic activity in the central nervous system correlates with cognitive decline in patients with Alzheimer's disease. The hypothesis resulted in the development of centrally-acting agents potentiating cholinergic neurotransmission; these drugs, however, only slowed down the cognitive decline and could not prevent it. Consequently, the perturbation of the central cholinergic signalling has been accepted as a part of the Alzheimer's aetiology but not necessarily the primary cause of the disease. In the present study we have focused on the rs3810950 polymorphism of ChAT (choline acetyltransferase) gene that has not been studied in Czech population before. METHODS:We carried out an association study to test for a relationship between the rs3810950 polymorphism and Alzheimer's disease in a group of 1186 persons; 759 patients with Alzheimer's disease and 427 control subjects. Furthermore, we performed molecular modelling of the terminal domain (1st-126th amino acid residue) of one of the ChAT isoforms (M) to visualise in silico whether the rs3810950 polymorphism (A120T) can change any features of the tertiary structure of the protein which would have a potential to alter its function. RESULTS:The AA genotype of CHAT was associated with a 1.25 times higher risk of AD (p?<? 0.002) thus demonstrating that the rs3810950 polymorphism can have a modest but statistically significant effect on the risk of AD in the Czech population. Furthermore, the molecular modelling indicated that the polymorphism is likely to be associated with significant variations in the tertiary structure of the protein molecule which may impact its enzyme activity. CONCLUSIONS:Our findings are consistent with the results of the meta-analytical studies of the relationship between rs3810950 polymorphism and AD and provide further material evidence for a direct (primary) involvement of cholinergic mechanisms in the etiopathogenesis of AD, particularly as a factor in cognitive decline and perturbed conscious awareness commonly observed in patients with AD.

Project description:Over the past two decades, the APOE gene and its polymorphisms have been among the most studied risk factors of Alzheimer disease (AD) development; yet, there are discrepancies between various studies regarding their impact. For this reason, the evaluation of the APOE genotype has not been included in the current European Federation of Neurological Societies guidelines for AD diagnosis and management. This aim of this study was to add to this discussion by assessing the possible influence of multiple polymorphisms in the promoter region of the APOE gene and genotypes of its allele E on the risk for dementia.We performed a comprehensive analysis of APOE gene polymorphisms, assessed the detected genotypes and correlated molecular findings with serum apolipoprotein E concentrations. The study comprised 110 patients with AD and 110 age-matched healthy individuals from the Polish population.Four polymorphisms of the APOE gene had minor allele frequency exceeding 5% and were included in the analysis: -491A/T (rs449647), -427T/C (rs769446), -219T/G (rs405509) in the promoter region and +113G/C (rs440446) in intron 1. A protective effect of the -219G allele on AD development was observed. Also, the -491T and -219G alleles were found to be underrepresented in the carriers of the APOE E4 variant. On the basis of the genotype and linkage disequilibrium studies, a relative score was attributed to given genotypes with respect to the estimated probability of their protective effects against AD, giving rise to the 'preventive score'. This 'preventive score', based on the total sums of the relative scores, expresses the protective effect deriving from the synergistic action of individual single-nucleotide polymorphisms. The 'preventive score' was identified as an independent predictive factor.We propose a novel, more complex approach to AD risk assessment based on the additive effect of multiple polymorphic loci within the APOE promoter region, which on their own may have too weak an impact to reach the level of significance. This has potentially practical implications, as it may help to improve the informative potential of APOE testing in a clinical setting. Subsequent studies of the proposed system in large, multi-ethnic cohorts are necessary for its validation and to assess its potential practical value for clinical applications.

Dataset Information

Polymorphisms of CHAT but not TFAM or VR22 are Associated with Alzheimer Disease Risk.

Publications

Polymorphisms of CHAT but not TFAM or VR22 are Associated with Alzheimer Disease Risk.

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