A genetic variation in the ADORA2A gene modifies age at onset in Huntington's disease ☆ Claire-Marie Dhaenens a,b,c, 1 , Sylvie Burnouf a,b, 1 , Clémence Simonin d , Edwige Van Brussel a,b , Alain Duhamel e , Luc Defebvre d , Cécile Duru f , Isabelle Vuillaume a,b,c , Cécile Cazeneuve g , Perrine Charles g,h , Patrick Maison h , Sabrina Debruxelles i , Christophe Verny j , Hélène Gervais k , Jean-Philippe Azulay l , Christine Tranchant m , Anne-Catherine Bachoud-Levi h , Alexandra Dürr g,h,n , Luc Buée a,b , Pierre Krystkowiak f,2 , Bernard Sablonnière a,b,c,2 , David Blum a,b, ⁎ ,2 and on behalf the Huntington French Speaking Network a Inserm, U837, Lille, France b Université Lille-Nord de France, USDL, IMPRT, Jean-Pierre Aubert Research Centre, Lille, France c UF Neurobiologie, Centre de Biologie Pathologie, CHRU Lille, France d Service de Neurologie et Pathologie du Mouvement, EA 2683, IMPRT, CHRU, Lille, France e CERIM, CHRU, Lille, France f Service de Neurologie, UMR CNRS 8160, CHU, Amiens University Hospital, Amiens, France g AP-HP, Departement de Genetique et Cytogenetique, Groupe Hospitalier Pitie-Salpetriere, Paris, France h AP-HP, Centre de référence maladie rare/maladie de Huntington, Créteil and Paris, France i CHU Bordeaux, Fédération de neurosciences cliniques et service de génétique médicale, Hôpital Pellegrin, Bordeaux, France j Département de Neurologie, CHU, Angers, France k Service de Neurologie, Hôpital Pierre Wertheimer, Lyon-Bron, France l Service de Neurologie et pathologie du mouvement, hôpital de la Timone, Marseille, France m Service de Neurologie, Hôpital Civil, Strasbourg, France n Inserm, UMR-S679, Paris, France abstract article info Article history: Received 27 May 2009 Accepted 28 June 2009 Available online 8 July 2009 Keywords: Huntington's disease A 2A receptors Polymorphism Based on the pathophysiological role of adenosine A 2A receptors in HD, we have evaluated the association of the 1976C/T single-nucleotide polymorphism in the ADORA2A gene (rs5751876) with residual age at onset (AAO) in HD. The study population consisted of 791 unrelated patients belonging to the Huntington French Speaking Network. The variability in AAO attributable to the CAG repeats number was calculated by linear regression using the log (AAO) as the dependent variable, and the respective rs5751876 genotypes as independent variables. We show that the rs5751876 variant significantly influences the variability in AAO. The R 2 statistic rose slightly but significantly (p =0.019) when rs5751876 T/T genotype was added to the regression model. Patients harbouring T/T genotype have an earlier AAO of 3.8 years as compared to C/C genotype (p = 0.02). Our data thus strengthens the pathophysiological role of A 2A receptors in Huntington's disease. © 2009 Elsevier Inc. All rights reserved. Introduction Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by involuntary movements, psychiatric disturbances and cognitive alterations (Roze et al., 2008). This disorder is fatal within 15–20 years after onset of symptoms. Although several cerebral regions show signs of neurodegeneration in HD, the primary and predominant neuropathological hallmark of this disorder is the atrophy of the striatum (Roze et al., 2008). HD is caused by a mutation within the IT15/HD1 gene encoding Huntingtin (The Huntington's Disease Collaborative Research Group, 1993). The mutation consists in a CAG triplet repeat expansion encoding an abnormal polyglutamine (polyQ) tract within the N-terminal region of the protein. HD patients harbour repetitions exceeding 35 repeats with complete penetrance above 38. Mutation in the IT15/HD1 gene statistically predicts for the age at onset (AAO), but on an individual basis, repeat length accounts for about 60% of its variance (Walker, 2007). For the most common expansions between 41 and 45 CAG repeats, the size of the CAG expansions even explains only 31% of the variance. These observations have led to a search for genetic factors Neurobiology of Disease 35 (2009) 474–476 ☆ Statistics performed by Dr. Alain Duhamel, MD, PhD, CERIM, CHRU, Lille, France (Academic). ⁎ Corresponding author. Inserm, U837, Jean-Pierre Aubert Research Centre,1 place de Verdun, 59045 Lille Cedex, France. Fax: +33320538562. E-mail address: david.blum@inserm.fr (D. Blum). 1 C-M.D and S.B equally contributed to this study. 2 P.K, B.S and D.B equally contributed to this study. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2009.06.009 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi