P.3.001 NMDA receptor co-determines vulnerability to develop dyskinesia in Huntington's Disease and levodopa-induced dyskinesia but not tardive dyskinesia

Abstract

Dyskinesia occurs as clinical feature of Huntington's Disease (HD) and as an adverse consequence of chronic exposure to levodopa in Parkinson's disease (levodopa-induced dyskinesia, LID) and to antipsychotic drugs in schizophrenia (tardive dyskinesia, TD). Arning et al. have reported that specific variations in the NR2A glutamate receptor subunit gene (GRIN2A) play a significant role in determining age at onset in HD [1]. These findings have been replicated by Andresen et al. [2]. This subunit of the NMDA glutamate receptor is assumed to play an important role in excitotoxicity of striatal Medium Spiny Neurons (MSN) resulting from over-activation of this receptor. Currently, there are no studies describing the relationship between GRIN2A polymorphisms and the vulnerability to develop drug-induced dyskinesia. Purpose: To investigate the association between TD/LID and 48 tagging SNPs from which 15 of the GRIN2A gene in Russian patients. Methods: After obtaining approval of the study protocol by the ethical committee, suitable participants were recruited from three psychiatric hospitals (Tomsk, Kemerovo, Chita) and the depart-ment of neurology of the Siberian State Medical University of Tomsk, Siberia (Russia). All subjects gave informed consent after proper explanation of the study. DNA extraction and Veracode Assay were conducted according to standard protocols. A total of 48 tagging SNPs were studied of which 15 of GRIN2A. The Abnormal Involuntary Movement Scale was utilized to define the presence of LID/TD. Logistic and logic regression on the binary measurement of dyskinesia (presence, absence) were performed to identify the effect of different variables, respectively SNP-SNP interactions. Results: In total 665 Russian Caucasian patients were included of who 144 were Parkinson's Disease (PD) patients from the neurological department [52 males, 92 females; age 63.1 ± 11.6 years (sample mean ± SD)]. Before analysis participants with more than 5 out of 48 missing SNPs were excluded. Moreover, SNPs with missing values that accounted for more than 10% of the sample were excluded from the analysis, leaving 41 SNPs for statistical analysis. The remaining missing values were imputed with random sampling from the marginal distribution of the proportions of the alleles in the patient population. In PD patients single-SNP logistic regressions identified 2 (rs7192557 and rs8057394) outof a total of 41 SNPs as most influential on the presence of LID on a 5% significance level, after correction for gender and duration of treatment. Logic regression showed that these two SNPs were present in most of the influential SNP combinations. SNP rs7192557 tags to rs1969060 identified by Arning et al. [1] and verified by Andresen et al. [2]. SNP rs8057394 was also identified in the verification study of Arning et al. [3]. The analysis on TD in schizophrenic patients did not identify these two SNPs as being influential. Conclusion: The same SNPs of the GRIN2A gene that play a role in the vulnerability to develop dyskinesias in Huntington Disease seem to be associated with the development of levodopa-induced dyskinesia in Parkinson's Disease but not of TD in schizophrenic patients, probably by determining the activity of the NMDA receptor on striatal MSN.