DBH −1021C→T does not modify risk or age at onset in Parkinson's disease

Abstract

DBH is a candidate gene in Parkinson's disease (PD) and contains a putative functional polymorphism (-1021C→T) that has been reported to modify PD susceptibility. We examined −1021C→T in a sample of 1,244 PD patients and 1,186 unrelated control subjects. There was no significant difference in allele (p = 0.14) or genotype (p = 0.26) frequencies between the two groups. A similar result was obtained after pooling our data with those previously published. Furthermore, we found no evidence for an effect of genotype on age at onset among patients. Our findings argue against DBH −1021C→T as a risk factor or age at onset modifier in PD.Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra and noradrenergic (NA) neurons in the locus ceruleus. 1 The clinical significance of central NA neuronal loss in PD is still debated, but one possible consequence is to render dopaminergic neurons more vulnerable to toxic insult.2 Support for this hypothesis comes from studies on animal models of PD in which prior lesioning of the locus ceruleus markedly enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-and 6-hydroxydopamine-mediated injury of nigral dopaminergic neurons.3 , 4 Thus, factors that modulate NA transmission might influence susceptibility or progression of PD.The DBH gene encodes the enzyme dopamine β-hydroxylase that converts dopamine to noradrenaline. Plasma activity levels of the enzyme vary 100-fold among European Americans, and a putative functional polymorphism (-1021C→T) in the DBH promoter accounts for approximately 50% of the variance. 5 Because the circulating enzyme is derived from neuronal sources, 6 −1021C→T might also serve as a marker for locus ceruleus dopamine β-hydroxylase content, which could affect NA outflow. Furthermore, DBH resides within a region on chromosome 9q with suggestive evidence of linkage for PD affection status and age at onset (AAO). In the only study published to date that has assessed the contribution of DBH −1021C→T to PD risk, Healy and colleagues 9 reported that the T/T genotype, which is associated with low levels of plasma dopamine β-hydroxylase activity, was protective against PD. We sought to replicate this finding in a large sample of well-characterized PD patients and control subjects. Subjects and Methods SubjectsThe study population comprised 1,244 PD patients (mean AAO, 57.9 ± 12.2 years; mean age at enrollment, 67.9 ± 10.6 years; male, 69.9%) and 1,186 unrelated control subjects (mean age at enrollment, 66.9 ± 14.1 years; male, 46.3%) of self-defined European American or "white" ancestry. All patients met standardized clinical diagnostic criteria for PD 10 as determined by a movement disorder specialist, and 16.2% reported having one or more first-degree relatives with PD. The PD cohort was consecutively recruited at six movement disorder clinics in the Portland, OR, and Seattle, WA, areas. Control subjects had no history of parkinsonism and were either spouses of PD patients or individuals recruited from the communit...

Dopamine β-hydroxylase −1021C>T association and Parkinson's disease

“…Two large association studies have examined the role of this functional SNP ( DBH -1021C>T; rs1611115) with PD susceptibility [8,9]. Healy et al (2004) reported a significant increase of the TT genotype in controls, thus protective against PD in a UK Caucasian population [9].…”

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]).…”

“…A meta-analysis of the association between DBH polymorphisms and PD risk included seven [28][29][30][31][32][33] studies involving a total of 3482 cases and 4086 controls, including four for rs1611115 [28][29][30][31], two for rs2519152 [32,33], and one for rs732833 [31]. The analysis results showed that no associations between a collection of all three DBH polymorphisms with susceptibility to PD was observed in three genetic patterns (allelic model: P = 0.899, dominant model: P = 0.994, and recessive model: P = 0.767, shown in Fig.…”

“…In this systematic analysis, a total of 41 studies involving 10506 cases and 15083 controls, including seven on AD [20][21][22][23][24], seven on PD [28][29][30][31][32][33], and twenty-seven on SCZ [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], were used in combination to investigate the association between a combination of all the available DBH polymorphisms and the development of diseases with neurodegenerative features, including AD, PD and SCZ. The combined results showed a lack of association between them under three genetic models (allelic model: P = 0.330, dominant model: P = 0.755, and recessive model: P = 0.509, shown in Fig.…”

“…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]. Conflicting results have also been published on variations of DBH rs2519152 [31] and other loci [29,31].…”