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Genetics
C08 Caffeine is a modifier of age at onset in Huntington's disease
  1. C Duru1,
  2. C Simonin2,
  3. F Richard3,
  4. P Hincker4,
  5. M Génin5,
  6. P Charles6,
  7. K Youssov7,
  8. S Burnouf8,
  9. J-P Azulay9,
  10. C Verny10,
  11. C Tranchant11,
  12. C Goizet1,2,
  13. L Defebvre2,
  14. B Sablonnière8,1,3,
  15. M Rousseau4,
  16. L Buée8,
  17. P Amouyel3,
  18. O Godefroy1,
  19. A Dürr6,7,
  20. A-C Bachoud-Lévi7,
  21. D Blum8,1,3,
  22. P Krystkowiak1 on behalf the Huntington French Speaking Network
  1. 1Service de Neurologie, Hôpital Nord, CHU Amiens, France
  2. 2Service de Neurologie et de Pathologie du Mouvement, EA 2683, IMPRT, CHU Lille, France
  3. 3Unité d'épidémiologie, Pôle de Santé Publique, CHU Lille, France
  4. 4Service de Nutrition, CHU Lille, France
  5. 5Unité de Biostatistiques, Pôle de Santé Publique, CHU Lille, France
  6. 6AP-HP, Service de Génétique et de Cytogénétique, Groupe Hospitalier Pitié-Salpétrière, Paris, France
  7. 7AP-HP, Centre de Référence Maladie Rare/Maladie de Huntington, Créteil et Paris, France
  8. 8Inserm, U837, Lille, France
  9. 9Service de Neurologie et de Pathologie du Mouvement, Hôpital de la Timone, Marseille, France
  10. 10Service de Neurologie, CHU Angers, France
  11. 11Service de Neurologie, Hôpital Civil, Strasbourg, France
  12. 12Service de Génétique, CHU Bordeaux, France
  13. 13Université Lille-Nord de France, USDL, IMPRT, Jean-Pierre Aubert Research Centre, Lille, France

Abstract

Background Phenotypic expression is variable in Huntington's disease (HD). 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 supporting the fact that 40% of the remaining variance is due to additional genetic and/or environmental factors. Association of AAO with polymorphisms located in different genes (ex: ADORA2A) has been previously reported. In contrast, whether environmental factors are also able to influence AAO remain unknown. Caffeine is a non-selective antagonist of A2A receptors, selectively localised on striatal medium spiny neurons expressing enkephalin and dopaminergic D2 receptors, known to be the most vulnerable ones in HD. Interestingly, modulation of A2A receptors influence the pathophysiological outcome in experimental models of HD.

Aims To determine the impact of caffeine on the AAO (primary endpoint) and the rates of functional, motor and cognitive decline (secondary endpoints) in HD patients.

Methods 58 HD patients were included from eight sites over a 6 month period. Information about caffeine consumption was collected with a validated self-questionnaire. All patients were evaluated using the Unified Huntington's Disease Rating Scale. Factors influencing AAO were examined using a stepwise regression analysis. After adjustment of CAG repeat length, subjects were categorised into three group and we compared the mean of AAO between low end high consumers.

Results We found a significant correlation between AAO and caffeine intake (r2=0.041; p=0.016): the highest caffeine intake was associated with the earlier AAO. Also, we demonstrated that caffeine influenced AAO with an advanced AAO of 6.9 years in high consumers compared with low consumers. However, we failed to demonstrate a relation between caffeine intake and the rate of functional, motor and cognitive decline.

Conclusion Our findings suggest that caffeine could be the first environmental modifier of AAO in HD. It could have an important therapeutic impact as the modulation of A2A receptors may represent new strategies for treating HD.

  • A2A receptors antagonist
  • caffeine
  • environmental factor

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