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

Abstract

BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsExtensive, 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.

Association between dopamine beta hydroxylase rs5320 polymorphism and smoking behaviour in elderly Japanese

“…21 The promoter polymorphism has been reported to be associated with Alzheimer's disease. 22 Several polymorphisms of DBH have been studied in terms of the association of smoking behaviour. Among them the promoter polymorphism À1021C/T (rs1611115) is the most extensively DBH in smoking behaviour of Japanese E Ella et al investigated as Zabeitian et al 23 reported this polymorphism as a functional polymorphism explaining inter-individual difference of plasma DBH activity.…”

Association of Dopamine Beta-Hydroxylase Polymorphisms with Alzheimer’s Disease, Parkinson’s Disease and Schizophrenia: Evidence Based on Currently Available Loci

“…These studies were published from 1996 to 2016. Among them, 25 studies involved Caucasian populations (AD: n = 5 [20][21][22], PD: n = 3 [28][29][30], SCZ: n = 17 [34-37, 44-46, 48]), and 16 studies involved Asian populations (AD: n = 2 [23,24], PD: n = 4 [31][32][33], SCZ: n = 10 [38-43, 47, 49]). Additionally, two diagnostic criteria were used among the AD studies included (DSM-IV [56] and NINCDS-ADRDA [57]), two criteria were used for PD studies (UK PD Society Brain Bank Clinical Diagnostic Criteria (UK-PDSBB) [58] and Standard for Second National conference on Cone Diseases), and three criteria were used for SCZ studies (DSM-IV [56], DSM-III-R [56] and ICD-10 [59]).…”

“…In this meta-analysis, a total of seven studies involving 2618 cases and 6849 controls, including five for rs1611115 [20][21][22][23][24], one for rs5320 and one for rs1611131 [20], were collected to investigate the association between DBH polymorphisms and AD development. Combined data revealed that the collection of DBH polymorphisms was not statistically significantly associated with the risk of AD under any of the three genetic models (allelic model: P = 0.714, dominant model: P = 0.837, and recessive model: P = 0.607).…”

“…Thus, it can be logically hypothesized that single nucleotide polymorphisms (SNPs) of DBH could be genetic markers of the risks of AD, PD and SCZ. Many GWAS and case-control studies have investigated the relationship of DBH polymorphisms with these three diseases, and it was even reported that DBH polymorphisms, such as variations in exons of rs1108580, rs5320, MspI, and rs4531 and introns of 5'-Ins/Del, rs1611115, rs1611131, and rs2519152, could play a role in the pathophysiologies of AD [20][21][22][23][24], PD [28][29][30][31][32][33] and SCZ [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. [28,30]; however, a recent genetic association research by Shao P. et al in 2016 indicated that the TT genotype may lead to a higher risk of PD occurrence than the common genotype CC [31].…”

“…An expected observation for risk variants is shared across diseases. Several genes are associated with AD, PD and SCZ and are included in the shared dopamine (DA) system network, including monoamine oxidase A (MAOA) [11][12], monoamine oxidase B (MAOB) [13][14][15][16], catechol-O-methyltransferase (COMT) [17][18][19] and dopamine beta-hydroxylase (DBH) [20][21][22][23][24]. Identification of these loci could help us better understand the mechanisms underlying the development of and cognitive dysfunction in AD, PD, and SCZ and provide biomarkers for their risk of susceptibility.…”