Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Marqués de Valdecilla University Hospital (University of Cantabria), 39008 Santander, Spain.
BMC Med Genet. 2010 Nov 11;11:162. doi: 10.1186/1471-2350-11-162.
The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine β-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 pro-inflammatory 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.
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.
蓝斑核去甲肾上腺素能神经元的丧失是阿尔茨海默病（AD）的主要特征。多巴胺β-羟化酶（DBH）催化多巴胺转化为去甲肾上腺素。据报道，DBH 的低活性-1021T 等位基因（rs1611115）与促炎细胞因子基因 IL1A 和 IL6 的多态性之间存在相互作用，这增加了 AD 的风险。因此，我们在 Epistasis 项目中检查了 DBH-1021T 等位基因与上述相互作用与 AD 的关联，该项目包括 1757 例 AD 病例和 6294 例老年对照。
我们对三个基因 DBH、IL1A 和 IL6 中的 8 个单核苷酸多态性（SNP）进行了基因分型。我们使用逻辑回归模型和协同因子分析来检查潜在的相互作用和与 AD 的关联。
我们发现-1021T 等位基因的存在与 AD 相关：比值比=1.2（95%置信区间：1.06-1.4，p=0.005）。这种关联几乎仅限于<75 岁的男性：比值比=2.2（1.4-3.3，0.0004）。我们还发现 DBH-1021T 的存在与 IL1A-889TT 基因型（rs1800587）之间存在相互作用：协同因子=1.9（1.2-3.1，0.005）。所有这些结果在北欧和西班牙北部都是一致的。
这里综述的广泛的先前证据表明，去甲肾上腺素在大脑炎症的控制中起着重要作用。因此，假定低活性的-1021T 等位基因可能与炎症的失调有关，这可能导致 AD 的发生。我们认为，这种失调是我们报告的关联的主要机制。
