P.5.d.005 - CYP2D6 and catechol-O-methyltransferase gene polymorphisms in Parkinson patients with levodopa-induced dyskinesias

Abstract

Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with levodopa (L-DOPA). Use of this drug, however, is severely limited by the development of side effect. 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 and monoamine metabolism, neurotransmitter receptors and proteins involved in oxidative stress or antioxidant function [2-4]. Objective: To investigate contribution of polymorphic variants of CYP2D6 and COMT genes in the development of LID in PD patients. Methods: 212 patients with Parkinson's disease on levodopa therapy were investigated. Dyskinesias were estimated with use of Abnormal Involuntary Movement Scale (AIMS). 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 2 SNPs of CYP2D6 (CYP2D6∗3, rs35742686; CYP2D6∗4, rs3892097) and 7 SNPs of COMT genes (rs4680, rs6269, rs4633, rs4818, rs769224, rs165774, rs174696). The SPSS software was used for statistical analysis. Results: Patients in our cohort demonstrated typical PD demographics, with a mean age of onset of 60.04±9.46 years, a mean disease duration of 9.79±5.57 years. Dyskinesias were reported in 57 (26.9%) patients. The distribution of genotypes of studied genes corresponded to the Hardy-Weinberg equilibrium. Association of polymorphisms in CYP2D6 gene with side effects was not revealed. We found that rs4680 polymorphism in COMT gene is significantly associated with LID (χ2 = 6.048, p = 0.049). Odds ratio for carriers of the genotype AA is 2.14 [95% CI: 1.11- 4.11], which indicates the predisposing effect of this genotype on the development of dyskinesias. Rs4680 is a functional SNP in genes encoding the catechol-O-methyltransferase enzyme, which catabolizes dopamine. A valine to methionine substitution at codon 158 of the COMT gene produces a Met variant that catabolizes dopamine up to four times slower than its Val counterpart. Conclusions: Polymorphisms in the COMT gene play significant role in the therapy response to L-DOPA as well as in various adverse effects. COMT is an extracellular enzyme which inactive variants increase the extracellular concentration of dopamine. This may increase the uptake of dopamine by indirect pathway MSN and therefore increase oxidative stress. We hypothesized that functional single nucleotide polymorphism rs4680 in COMT gene may result in a clinical phenotype contributing to an increased risk of LID. Thus, the polymorphism of gene possessing predisposing effects in development of levodopa induced dyskinesia in PD has been revealed that would allow predicting risk of development of movement disorders.