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Genetic modifiers
E03 Association study of cannabinoid receptor gene (CNR1) polymorphisms and age at onset in HD
  1. E Kloster1,2,
  2. C Saft3,
  3. L Arning1
  1. 1Department of Human Genetics, Faculty of Medicine, Ruhr-University Bochum, Bochum, Germany
  2. 2Ruhr-University Bochum, International Graduate School of Neuroscience, Bochum, Germany
  3. 3Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany


Background Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene. Although the variation in age at onset (AO) is partly explained by the lengths of the expanded repeat, the unexplained variation in AO is heritable, emphasising the role of modifier genes on disease expression. Identification of modifier genes can confirm intracellular pathways already suspected to be involved in pathophysiological processes related to HD pathogenesis. Since down regulation of type 1 cannabinoid (CB1) receptors is a key pathogenic event in HD, it has been suggested that activation of these receptors in patients may attenuate disease progression.

Aims In order to evaluate whether variations in the cannabinoid receptor 1 (CNR1) gene encoding the CB1 receptor have modifying effects on the AO of HD we performed an association study between CNR1 polymorphisms and AO in HD patients.

Results/outcome AO was significantly associated with the longest alleles (≥17 AAT) of the (AAT)n triplet repeat polymorphism downstream of the CNR1 gene (p=0.02), as well as with one single nucleotide polymorphism (SNP) in the 3′UTR of CNR1 (rs4707436, p=0.05).

Methods/techniques A total of nine SNPs in the CNR1 gene were selected for genotyping in a German HD cohort of more than 500 patients recruited from the Huntington Center NRW in Bochum. Genotyping was performed by restriction fragment length polymorphism (RFLP). The (AAT)n repeat polymorphism was genotyped by capillary electrophoresis using Beckman-Coulter CEQT 8000 Genetic Analysis System. Variability in AO was assessed by linear regression using logarithmically transformed AO as dependent and respective genotypes as independent variables.

Conclusions These data support the idea that variation in CNR1 may have modifying effects on the AO in HD.

  • Genetic modifier
  • cannabinoid receptor 1

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