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

DOI: 10.1186/1471-2350-11-162

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Abstract:

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.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.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.The loss of noradrenergic neurones of the locus coeruleus is a striking feature of sporadic Alzheimer's disease (AD). A gradual, moderate loss is found with ageing in healthy people [1-3], but a more dramatic loss is seen in AD. A meta-analysis [4] showed similarly high losses of noradrenergic neurones (24 studies) as of cholinergic neurones (33 studies), with losses four times greater than those of dopaminergic cells in AD. Noradrenergic neurones project from the brainstem to innervate wide areas of the forebrain [5]. Levels of noradrenaline (NA, norepinephrine) in target regions have also sometimes been reported lowered in ageing [6,7], e.g. in the hippocampus and hypothalamus. They have generally been found to be further reduced in AD [8-13], e.g. in the hippocampus, hypothalamus, caudate nucleus, putamen and neocortex, although not in one small study [14]. Both the loss of noradrenergic neurones [15] and that of NA in target re

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