P.5.d.005 Polymorphisms of DRD2, DRD3, DRD4 and HTR2C genes in levodopa-induced dyskinesias in Parkinson's disease

Abstract

Levodopa-induced dyskinesias (LID) are involuntary muscle movements that occur as a consequence of chronic levodopa (L-DOPA) treatment. LID are a substantial barrier to effective symptomatic management of Parkinson's disease (PD), up to 45% of L-DOPA users develop LID within 5 years [1]. Clinical heterogeneity of LID suggests a significant role of endogenous factors in determining their prevalence. Some evidence suggest a relationship between LID and specific genetic changes, such as changes in the genes controlling enzymes responsible for drug metabolism, neurotransmitter receptors, as well as proteins involved in oxidative stress or antioxidant function [2]. Our previous results showed that the susceptibility to LID was associated with two NMDA receptor (GRIN2A) variants [3]. Objective: To investigate contribution of polymorphic variants of HTR2C serotonin receptor gene and DRD2, DRD3 and DRD4 dopamine receptors genes in the development of LID in PD patients. Methods: 143 patients with Parkinson's disease were examined. Dyskinesias were estimated with use of Abnormal Involuntary Movement Scale (AIMS). Orofaciolingual LID (LIDof) and limb-truncal LID (LIDlt) were assessed with AIMS items 1-4 and 5-7, respectively. DNA extraction and fluorogenic 5- exonuclease TaqMan genotyping assays were conducted according to standard protocols and blind to the clinical status of the subjects. Genotyping was carried out on 23 polymorphic variants of DRD2, DRD3, DRD4 and HTR2C genes (rs6275, rs1800497, rs1799732, rs71653615, rs11721264, rs167770, rs3773678, rs963468, rs7633291, rs2134655, rs9817063, rs324035, rs1800828, rs167771, rs3758653, rs6318, rs5946189, rs569959, rs17326429, rs4911871, rs3813929, rs1801412, rs12858300). The softwares “R” and SPSS were used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. For the SNPs in the X-chromosomal HTR2C gene, deviation from HWE was not calculated. Results: Associations of 5 polymorphisms with levodopainduced dyskinesias in patients with PD were revealed. Polymorphisms associated with orofaciolingual LID virtually did not overlap with polymorphisms associated with limb-truncal LID, indicating the different genetic basis of these phenotypes. Moreover, LIDof and LIDlt are associated with different genes polymorphisms. LIDof is associated with DRD4 (rs3758653) and HTR2C (rs4911871, rs5946189) genes polymorphisms whereas LIDlt is associated with only one of studied polymorphism. Polymorphisms of DRD3 gene (rs2134655, rs963468) are associated with severity of dyskinesia: rs2134655 - with orofaciolingual LID; rs963468 - with limb-truncal LID, but not with the fact of the presence of dyskinesia itself. Conclusions: Polymorphisms in the genes coding for neurotransmitter receptors play significant roles in the therapy response to L-DOPA as well as in various adverse effects. We hypothesised that single nucleotide polymorphisms in specific genes, particularly those coding for dopamine and serotonin receptors, may result in a clinical phenotype contributing to an increased risk of LID. Thus, the polymorphisms of genes possessing protective or predisposing effects in development of levodopa induced dyskinesia in PD have been revealed that would allow predicting risk of development of movement disorders.