Opioid K receptor variant delays the onset of dyskinesias in Parkinson's disease

Objective:To investigate the genetic factors modulating the timing of the onset of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD).Background: Pathophysiological mechanisms underlying LIDs may share similarities with non-motor conditions related to DA overstimulation, such as addiction.Methods: 284 PD patients (mean age at onset 52.5 6 9.8 ys) who participated to Parkinson's Institute BioBank and developed LIDs during the disease course (mean follow-up duration 10.0 6 4.5 ys) were consecutively genotyped. Patients were stratified according to disease durationat the onset of LIDs. Ten SNPs were investigated according to literature on addiction in non-PD population: Dopaminergic (DAT, DRD1, DRD2,DRD3); Catecholaminergic (COMT); Serotonergic (TPH2); Opioidergic(OPRM1, OPRK1); Glutamatergic (GRIN2B). Statistical Analysis. A standard case-control analysis using allelic/genotypic chi-square test was used to provide asymptotic p values, OR and 95%CI for minor alleles. Values of p<0.005 for allelic and p <0.0017 for genotypic association analyses were considered as statistical significant after Bonferroni correction for multiple testing. Kaplan-Meier curves of PD duration free of LIDs for OPRK1 genotypes were computed. Multivariate linear regression analysis was used to identify independent predictors of PD duration at the onset of LIDs.Results: Allelic and genotypic analyses showed a significant association between earlier onset of LIDs and the rs1051660 variant on the OPRK1 gene (p50.0019 and p50.00168, respectively). PD carriers of the A allele on the OPRK1 gene had a 1.5-year delay in the onset of LIDs (mean disease duration LIDs 8.4 vs. 10.0 ys, p50.003). Multivariate analysis confirmed the significant effect of the A allele of OPRK1 gene (p50.021), along with younger age at onset and disease progression. Kaplan-Meier estimates of the probability of LIDs showed significant effect of OPRK1 genotype (Logrank test p 0.0118).Conclusions: This is the largest cohort of PD with LIDs genotyped so far with such a long clinical follow-up. Our preliminary results suggest that genetic variants of opioid K receptors modify the risk of dyskinesias in PD. Opioid K receptors signaling reduce DA release in the striatum and, in animal models, K receptor agonists reduce LIDs. These data support further research on the relationship between K opioid transmission and LIDs in PD.