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The dopamine beta-hydroxylase-1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project

Combarros, O; Warden, DR; Hammond, N; Cortina-Borja, M; Belbin, O; Lehmann, MG; Wilcock, GK; ... Lehmann, DJ; + view all (2010) The dopamine beta-hydroxylase-1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project. BMC Medical Genetics , 11 , Article 162. 10.1186/1471-2350-11-162. Green open access

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Abstract

Background: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine beta-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the proinflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls.Methods: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD.Results: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain.Conclusions: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

Type: Article
Title: The dopamine beta-hydroxylase-1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/1471-2350-11-162
Publisher version: http://dx.doi.org/10.1186/1471-2350-11-162
Language: English
Additional information: © 2010 Combarros et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: BETA-HYDROXYLASE ACTIVITY, BDNF MESSENGER-RNA, I-KAPPA-B, LOCUS-COERULEUS, NORADRENERGIC SYSTEM, OXIDATIVE STRESS, HIPPOCAMPAL-NEURONS, CHOLINERGIC NEURONS, NEUROTROPHIC-FACTOR, PARKINSONS-DISEASE
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1322352
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