Open Access Highly Accessed Research article

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

Onofre Combarros1*, Donald R Warden2, Naomi Hammond3, Mario Cortina-Borja4, Olivia Belbin5, Michael G Lehmann2, Gordon K Wilcock6, Kristelle Brown5, Patrick G Kehoe7, Rachel Barber7, Eliecer Coto8, Victoria Alvarez8, Panos Deloukas3, Rhian Gwilliam3, Reinhard Heun109, Heike Kölsch9, Ignacio Mateo1, Abderrahim Oulhaj11, Alejandro Arias-Vásquez1213, Maaike Schuur1214, Yurii S Aulchenko12, M Arfan Ikram12, Monique M Breteler12, Cornelia M van Duijn12, Kevin Morgan5, A David Smith2 and Donald J Lehmann2

Author Affiliations

1 Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), 39008 Santander, Spain

2 Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK

3 The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

4 Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK

5 School of Molecular Medical Sciences, Institute of Genetics, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK

6 Nuffield Department of Medicine, University of Oxford, Level 4, John Radcliffe Hospital, Oxford OX3 9DU, UK

7 Dementia Research Group, Institute of Clinical Neurosciences, University of Bristol, Frenchay Hospital, Frenchay Bristol, BS16 1LE, UK

8 Genética Molecular, Hospital Central de Asturias, Oviedo, Spain

9 Department of Psychiatry, University of Bonn, Bonn, Germany

10 Royal Derby Hospital, Uttoxeter Road, Derby DE22 3NE, UK

11 OPTIMA, Nuffield Department of Medicine, University of Oxford, Level 4, John Radcliffe Hospital, Oxford OX3 9DU, UK

12 Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands

13 Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior & Department of Human Genetics, Radboud University Nijmegen, Medical Centre, P.O. Box 9101, HP 966, Nijmegen 6500 HB, The Netherlands

14 Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands

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BMC Medical Genetics 2010, 11:162  doi:10.1186/1471-2350-11-162

Published: 11 November 2010

Abstract

Background

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.

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.